The IZKF Aachen in 2011 - RWTH Aachen University

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The IZKF Aachen in 2011 - RWTH Aachen University
PROGRESS REPORT 2011
Interdisciplinary Center of Clinical Research
of the RWTH Aachen Faculty of Medicine
Progress Report IZKF Aachen 2011
Preface
Chair
of the IZKF Aachen
Top (from left to right)
Prof. J. Bernhagen, Prof. M. Zenke, Prof. H. Fischer, Prof. J. Weis, Prof. A. Schober, PD Dr. F. Tacke,
Prof. A. Ludwig, K. De Bruyne (guest)
Bottom (from left to right)
Prof. T. Gries, Prof. B. Lüscher, Prof. P. Walter, Prof. U. Habel
Further board member, not pictured:
Prof. G. Thumann
IZKF Aachen Progress Report 2011
Preface
Preface
Prof. Dr. Peter Walter
(Speaker of the IZKF)
Dear Colleagues.
The IZKF Aachen resembles the strategic intramural funding programme of the RWTH Aachen
University Faculty of Medicine. It consists of
measures for funding research projects supporting the main research topics of the Faculty but it
also hosts and manages Core Facilities open to
all researchers of the Faculty of Medicine. The
IZKF Aachen also funds research groups supporting the strategic goals of the Faculty.
This Annual Report 2011 summarizes the efforts
and the results of IZKF Aachen. The year 2011
represents the end of the three-year funding
period, which started in July 2008. It also represents the start of the new funding period, which
will last until June 2014. The year 2011, therefore,
was a very busy and important year for us. After
intensive discussions during the review process
and after two days of on-site evaluation with
the members of our Scientific Advisory Board,
new projects were initiated and re-organization
measures for the Core Facilities were activated.
One major aspect of the re-organization of the
Core Facilities is the development of concepts for
partly financing these units through suitable user
fees. In addition to the existing Core Facilities in
2011 we established the Proteomics Core Facility.
During the on-site evaluation in February 2011, our
Scientific Advisory Board confirmed the quality of
the concept and the strategy of the IZKF.
In 2011, we also started the selection process
for four new Research Groups with a focus
on the main research topics of the Faculty of
Medicine. The groups will start in 2012 with
significant funding from the IZKF. Among these
groups one will focus on bioinformatics, which
will help to close a relevant gap within the
biomedical Aachen research community. This
group will also be supported by the Jülich Research Center and by RWTH Aachen University.
In January 2012, the members of IZKF Aachen
elected the new Board and I have the honour to
serve for another three years as the Chair of the
IZKF Board.
In the past year I had the opportunity to share
ideas and to discuss progress with brilliant and
hard working people not only in the Board of the
IZKF but also among the members of the IZKF,
with the Core Facility heads and with the fantastic staff in the IZKF central units. The work
of the IZKF was strongly supported by the Dean
of the Faculty of Medicine Professor Uhlig, and
also by people in the Aachen University Hospital
administration. I also have to thank the members
of our Scientific Advisory Board, namely its Chair
Professor Peters, for their invaluable help in
improving the processes and outcomes of the
IZKF Aachen.
Many relevant problems could be solved in 2011
by cooperative strategies and the IZKF Board
will continue on its way to make the IZKF story a
success story for the Medical Faculty.
Prof. Dr. Peter Walter
IZKF Aachen Progress Report 2011
Imprint
Publisher:
Interdisciplinary Center of Clinical Research (IZKF Aachen)
Speaker: Prof. Peter Walter
Pauwelsstraße 30
D-52074 Aachen
Phone: +49 241 80 80034
Email: [email protected]
www.izkf-aachen.de
Editor:
Layout:
Printing:
Print Run:
Karen De Bruyne M.A. (administration office)
sabinebergs Konzept + Design, Kreuzau
Druckerei Mainz, Aachen
150 copies
Aachen, May 2012
The project leaders are responsible for the content of their reports and for the information on their
external funding, publications, etc.
IZKF Aachen Progress Report 2011
Contents
Contents
Progress Report 2011
1.
General Information
1.1.
1.2.
Function and Goals of the IZKF
The IZKF Aachen in 2011
2.
Project Funding
2.1.
2.2.
2.3.
2.4.
Research Focus Area 1: Medicine and Technology
Research Focus Area 2: Cardiovascular Research
Research Focus Area 3: Clinical Neurosciences
Research Focus Area 4: Inflammation and Consequences
8
42
64
108
3.
Funding Young Researchers
150
3.1.
3.2.
3.3.
Young Researcher Groups
Junior Research Projects
Diploma Theses, Doctoral Theses and Postdoctoral Lecture Qualification
152
158
176
4.
Core Facilities
186
4.1.
4.2.
4.3.
4.4.
4.5.
4.6.
Core Laboratory
Chip Facility
Immunohistochemistry and Confocal Laser Scanning Microscopy Facility
Brain Imaging Facility
Two-Photon Imaging Facility
Transgenic Service
188
191
196
200
204
207
5.
Annual Report
210
5.1.
5.2.
5.3.
5.4.
Funding
Participating Institutes and Clinics
Output and Evaluation
Structure and Responsibilities
212
216
219
220
6.
Publications 2011
229
2
5
Thematically based on the Main Research Focus Areas
of the Faculty of Medicine
Career Advancement from Doctoral Thesis to
Young Researcher Group Leading
Equipment and Expertise – Service for Research
IZKF Aachen Progress Report 2011
1.1.
General Information
|
Function and Goals of the IZKF
Function and Goals of the IZKF
Established in 1995, the Aachen Interdisciplinary Center for Clinical Research (IZKF) is one of six
nationwide IZKFs at universities (Aachen, Erlangen, Jena, Köln, Münster and Würzburg) today.
All of the IZKFs emerged from the Federal Ministry of Education and Research’s initiative “Health
Research 2000”. Every center developed its own research focus areas and structures.
The task and goal of the IZKF Aachen is to strengthen the translational medical research stemming
from its basic research and clinic. The IZKF at UKA considers itself as a development and strategy
program of the RWTH Faculty of Medicine. By supporting first class research projects, it strives to
greatly improve chances for fundraising high amounts of external funding.
Mission Statement
of the IZKF Aachen
Four Research Focus Areas
Two Step
Evaluation Process
2
IZKF Aachen Progress Report 2011
The mission of the IZKF Aachen is to improve the overall quality of the translational medical research, emanating from both fundamental and clinical research.
The main focus is placed on:
• project funding
• funding of young researchers
• funding of core facilities
The central aim is always the strategic further development of the Faculty of Medicine of RWTH Aachen.
As stipulated by the constitution, the IZKF Aachen
research focuses correspond to those of RWTH
Aachen’s Faculty of Medicine:
• Medicine and Technology
• Cardiovascular Research
• Clinical Neurosciences
• Inflammation and Consequences
In some exceptions, projects also can be funded independently from these research focus areas.
A funding period in the IZKF Aachen stretches over
three years. The current funding period is from
July 2011 to June 2014. Depending on the available
budget, projects with a shorter funding period can be
granted during the actual funding period.
General Information
|
Function and Goals of the IZKF
1.1.
IZKF Aachen Progress Report 2011
3
The IZKF Aachen exclusively funds research
projects from researchers, who have already acquired
external funding and have published material relevant
to the project.
Start-up funding for the start of a research career can
be applied for through the START-program.
All project submissions are reviewed through a two
step evaluation process, which takes their research
quality and feasibility into consideration.
In a first step the internal research council evaluates
the project outlines. The research council is composed
of 12 professors from the RWTH Faculty of Medicine
and represents the research areas the Faculty focuses
on. Thorough and complete research proposals receive
the highest evaluation. A ranking is generated from the
advisory opinions, on the basis of which the IZKF chair
calls candidates to submit a complete proposal. The
funding amount of individual proposals is not fixed.
In a second step the external research advisory
board evaluates the complete proposals and is responsible for final funding decisions. The advisory board
represents the focuses of the IZKF Aachen and is made
up of five domestic and/or international researchers per
focus, who do not belong to the Faculty of Medicine or
RWTH. For each focus, the advisory board can temporarily bring in three further evaluators from within Germany, abroad, or the industry.
Negative votes of the external research advisory
board are binding. The number of approved projects is
determined by the yearly budget of the IZKF of € 4.3 M,
eventually added with reserve funds of the last
funding period.
1.1.
General Information
|
Function and Goals of the IZKF
Young Researcher Funding
Core facilities:
Equipment and Expertise
– Service for Research
4
IZKF Aachen Progress Report 2011
The Aachen IZKF offers ambitious researchers with
outstanding achievements an attractive possibility
for funding through its young researchers group. The
young researchers groups are assigned to a clinic or
institute and can independently work there. The group
heads are essentially freed from their clinical responsibilities and can immediately devote themselves to
research. Currently two groups for young researchers
are being funded. Group leaders are equipped with
first class research qualification, experience in acquiring external funding, and are chosen by the IZKF chair
through a selection symposium. After a positive evaluation after an initial period of three years, the funding can
be extended for another three years.
In addition to project funding and young researcher
funding, the IZKF also funds the equipment and
carrying out of “Core Facilities”: central service units,
in which equipment, expertise, and methods are available. The Core Facilities are available for all members
of the Faculty of Medicine and are a valuable resource
for an effective research environment.
General Information
| The IZKF Aachen in 2011
1.2.
The IZKF Aachen in 2011
In mid 2011, the regular three-year funding period ended. This progress report contains the final
reports of the funded projects.
After the new funding period was prepared and after the internal evaluation of the projects took
place in the previous year, the evaluation process has been pursued for the period 2011-2014 with
the on-site evaluation of the Scientific Advisory Board. On July 1st, new projects also started for a
period of three years.
The enhancement of the Core Facilities and the preparation of the establishment of new Researcher
Groups also were relevant issues.
In preparation for the on-site evaluation the members of
the Scientific Advisory Board obtained 35 proposals with
a requesting funding volume of € 2 M and 6 proposals
for the continuation, respectively for the establishment
of Core Facilities with a requesting funding volume of
€ 1.18 M. Each proposal was assigned three evaluators for evaluation. The joint research projects were
presented by an oral presentation. All subprojects and
individual projects were presented and discussed within the framework of a poster presentation. By visiting
the Core facilities on-site the Scientific Advisory Board
used the opportunity to discuss the equipment and
the offered services with the Core Facility Heads and
the Scientific Supervisors. After the public portion the
members of the Scientific Advisory Board held internal
meetings to evaluate each proposal. All in all the IZKF
received a very positive evaluation. Four projects were
not recommended for funding. Two proposals could
be revised and will have another chance in a second
evaluation in 2012.
In a meeting with the Board, the Heads and the
Scientific Supervisors of the Core Facilities the strategy, management structures, concepts of partly refinancing, user regulations and external presentation
were discussed and developed. The position of the
Head of the Brain Imaging Facility was refilled with
Dr. Mingoia. With the selection of Dr. Preisinger, the
first steps were taken for the establishment of the new
Proteomics Facility.
On-site evaluation of the
Scientific Advisory Board
Enhancement of the
Core Facilities
IZKF Aachen Progress Report 2011
5
1.2.
General Information
| The IZKF Aachen in 2011
Selection process for
four new Research Groups
A work group consisting of board members developed
a concept for the new “Research Groups”. Intentionally the board abandoned the term “Young” Research
Groups, because more than the age of the heads, it
was important to the board to bring important expertise to Aachen that had been absent in the Faculty
of Medicine thus far. Though cross-sectoral themes
were defined previously, a general advertisement was
published under specification of the four research
focus areas and the indication that specific emphasis
will be laid on state of the art technologies and expertise
bridging these areas. Supported by the Jülich Research
Center and the RWTH Graduate School „Aachen
Institute for Advanced Study in Computational
Engineering Science (AICES), the board decided to
establish one of the groups focusing on “Bioinformatics”,
because of its importance for biomedical research.
The Research Groups will be affiliated with “hosting”
clinics or institutes, who will provide the needed infrastructure. In 2012, up to four “Research Groups” will be
established, each with a budget of up to € 200,000.
The groups will be funded for a period of three years,
with the possibility of extension for another three
years after a positive evaluation. Scientific excellence
was the main criterion during the selection procedure
for the heads of the Research Groups. Though internal candidates were not excluded from the selection
procedure, the board particularly expected additional
expertise for Aachen from the selection of the candidates. Twelve candidates presented their research
orally during a public selection symposium. At the end
of the year the decision was taken to establish four new
Research Groups with the topics “Bioinformatics”,
“Cardiovascular Research”, “Clinical Neurosciences”
and “Inflammation and Consequences” under the
direction of four excellent heads in the year 2012.
6
IZKF Aachen Progress Report 2011
General Information
| The IZKF Aachen in 2011
1.2.
2011 Funding Measures in a Nutshell
Project Funding
62 projects (42 within the scope of joint research projects)
(44% of the total budget during the report period)
Supporting of Junior Scientists
12 Junior Research Projects
2 Junior Research Groups
(22%of the total budget during the report period)
Core Facilities / Laboratory
Core Laboratory
Chip Facility
Immunohistochemistry & Confocal Laser Scanning Microscopy Facility
Brain Imaging Facility
Two-Photon Imaging Facility
Transgenic Service
(26%of the total budget during the report period)
8 percent of the total budget during report period was expended for the scientific coordinating office
and central costs.
IZKF Aachen Progress Report 2011
7
IZKF Aachen Progress Report 2011
PROJECT FUNDING
Medicine and Technology
In 2011, the IZKF funded 12 projects with € 261,511 in the research
focus area Medicine and Technology.
IZKF Aachen Progress Report 2011
2.1.
Project Funding
|
Medicine and Technology
PROJECT FUNDING
Medicine and Technology
FINAL REPORTS
10
T1 | Sechi | 01.07.2008 - 30.06.2011
Biomaterial-induced alterations of DC functions and their implication in the onset
of inflammatory and fibrotic responses to medical implants
p. 12
T2 | Zenke | 01.07.2008 - 30.06.2011
Reprogrammed hematopoietic stem cells in nanostructured 3D scaffolds
p. 14
T3 | Günther | 01.07.2008 - 30.06.2011
Plasmacytoid dendritic cells and plaque instability
p. 17
T4 | Noels | 01.07.2008 - 30.06.2011
Role of platelets and platelet-derived chemokines in the recruitment
of dendritic cells
p. 19
T5 | Noels | 01.07.2008 - 30.06.2011
Imaging and role of junctional adhesion molecule (JAM) A in atherogenic
pathogenesis
p. 21
T6 | Jockenhövel | 01.07.2008 - 31.12.2011
The vital stent – novel composite structure of self-expanding stent & tissue
engineered vessel
p. 23
T7 | Zenke | 01.07.2008 - 30.06.2011
Labelling of stem cells and immune cells with functionalized iron-oxide
nanoparticles for in vivo cell tracking
p. 26
T8 | Kiessling | 01.07.2008 - 30.06.2011
Combination of OCT and NIRF-OT for improving diagnosis in carcinoma
p. 28
IZKF Aachen Progress Report 2011
Project Funding
|
Medicine and Technology
2.1.
PROGRESS REPORTS
p. 30
T9 | JOINT RESEARCH PROJECT Fischer | 01.07.2011 - 30.06.2014
Mechanobiology
T9-1 | Fischer | 01.07.2011 - 30.06.2014
Development of tailored mineral 3D scaffolds for suitable treatment of bone
defects of elderly patients
p. 33
T9-2 | Leube | 01.07.2011 - 30.06.2014
The function of the desmosomal cadherin desmoglein 2 for cardiac force
transmission and force generation
p. 35
T9-3 | Pufe | 01.07.2011 - 30.06.2014
The potential of mechanically stimulated programmable cells of monocytic
origin in cartilage regeneration
p. 37
T10 | Zenke | 01.07.2011 - 30.06.2014
The impact of biomaterial surface topology on differentiation of pluripotent stem
cells into cardiomyocytes
p. 39
IZKF Aachen Progress Report 2011
11
2.1.
Project Funding
|
Medicine and Technology
| T1
Biomaterial-induced alterations of DC functions and their
implication in the onset of inflammatory and fibrotic
responses to medical implants
Sechi A. (Institute of Biomedical Engineering – Cell Biology)
Zenke M. (Institute of Biomedical Engineering – Cell Biology)
The use of a biomaterial (i.e. an implant) is often
associated with a response from the host immune
system leading to inflammatory and fibrotic reactions. As such reactions sometime lead to defective implant functionality, to reduce or eliminate
them it is essential to understand the effect of
biomaterials on immune cells. Hence, this project
was centred on the characterisation at molecular
level of the interactions between chemically and
physically diverse biopolymers and the dendritic
cell (DC), an immune cell type that is essential for the regulation of the immune response.
Figure 1. Potential role of DCs in the development of the foreign body reaction (FBR). The interaction of
DCs with biomaterials or their degradation products mediated by Toll-like receptors leads to alteration of
surface markers, adhesion, and cytokine secretion (boxed panels; left to right, respectively) in these cells.
At the implantation site, stimulated DCs may directly affect the immune system homeostasis, thus initiating
or sustaining the events (cytokine release, fibroblast proliferation, inflammatory and fibrotic responses)
leading to FBR and implant malfunction. FBR (and implant malfunction) could also be a consequence of
the alteration of the function of macrophages, neutrophils and T cells (all known to be involved in FBR
development) induced by stimulated DCs.
12
IZKF Aachen Progress Report 2011
Project Funding
|
Medicine and Technology
| T1
2.1.
Funding period: 01.07.2008 - 30.06.2011
Staff: ½ TV-L 13 (Shokouhi, B.)
Materials 2011: € 1,700
Investments/Equipment 2011: –
We found that changes in the expression of activation markers and cytokines in these cells depend on sensing mechanisms that involve several
Toll-like receptors (TLRs), in particular TLR2 and
TLR4. TLR-biomaterial interactions are also sufficient to make DCs capable to activate T cells and
assemble special contact sites (i.e. podosomes)
with substrates. Furthermore, biopolymers affect
DC function also through degradation products
(soluble polymer molecules), likely following the
engagement of endosomal TLR7 and TLR9 receptors. Since DCs are known to regulate the
function of other immune cells, such as macrophages, neutrophils and T cells (all of which are
involved in the development of fibrotic reactions),
our findings suggest that the biomaterial-induced
alteration of DC function may contribute to inflammatory and fibrotic reactions at the implantation
site. We are currently testing this hypothesis using in vivo mouse models.
In the context of structure-function studies, the
knowledge we generated in this project could be
exploited for developing more bioinert materials.
In addition, novel biopolymers able to specifically
activate single or multiple TLRs could be used to
control DC function, thus triggering specific immune responses.
Publications
IZKF relevant, project associated
1. Würflinger, T., Gamper, I., Aach, T. and Sechi,
A.S. (2011). Automated segmentation and
tracking for large scale analysis of focal adhesion dynamics. J. Microsc. 241: 37-53. [IF:
1.872]
2. Ferreira MV, Labude N, Piroth D, JahnenDechent W, Knüchel R, Hieronymus T, Zenke
M, Neuss S. (2011). Compatibility of different
polymers for cord blood-derived hematopoi-
etic progenitor cells. J Mater Sci Mater Med.
doi:10.1007/s10856-011-4483-4. [IF: 2.325]
3. Neuss S, Denecke B, Gan L, Lin Q, Bovi M,
Apel C, Wöltje M, Dhanasingh A, Salber J,
Knüchel R, Zenke M. (2011). Transcriptome
analysis of MSC and MSC-derived osteoblasts
on Resomer® LT706 and PCL: impact of biomaterial substrate on osteogenic differentiation. PLoS One. 6:e23195. [IF: 4.411]
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
04/200806/2011
€ 518,800
TGF-beta/Id2 signalling in development DFG/SFB 542
of antigen presenting dendritic cells
B10
07/200806/2011
€ 377,100
Reprogramming of and programming
by mesenchymal stem cells (MSC)
11/201010/2013
€ 195,000
Zenke, M.
Reprogramming and somatic memory
in ES cell/hematopoietic cell hybrids
Zenke, M.
Zenke, M.
DFG Ze 432/51/2
DFG Ze 432/6-1
Promoting of young researcher
Doctoral Theses
Behnaz, S.
2011
RWTH Aachen,
Faculty 1
Influence of biomaterials on dendritic cell function
IZKF Aachen Progress Report 2011
13
2.1.
Project Funding
|
Medicine and Technology
| T2
Reprogrammed hematopoietic stem cells in nanostructured
3D scaffolds
Zenke M. (Institute of Biomedical Engineering – Cell Biology)
Neuß-Stein S. (Institute of Pathology)
In our previous work we found that biomaterials
impact a variety of stem cell types (Neuss et al.,
Biomaterials, 2008). In following up on this observation, the objective of this project was to identify
polymers that (i) support feeder-free growth of
pluripotent stem cells, such as mouse embryonic
stem cells (ES cells), somatic cell/ES cell hybrids
and induced pluripotent stem cells (iPS cells) and
that (ii) foster a specific differentiation fate of such
cells, in particular cardiomyogenic differentiation.
Therefore, stem cells were cultured on a panel
of biopolymers and synthetic polymers of our
Biomaterial Bank (established in our former IZKF
project VVB110) and different parameters, such
Figure 1: Biocompatibility of polymers for
stem cells. (A) Results of cell-based assays
with different stem cell types for cell vitality, cytotoxicity and apoptosis are depicted in heat map
format. (B) Summary of polymers, which (i) support stem cell adhesion, vitality and proliferation
and (ii) inhibit cytotoxicity and apoptosis. DPSC,
human dental pulp stem cells; EPC, human endothelial progenitor cells; hMSC, human mesenchymal stem cells; mMSC, mouse mesenchymal
stem cells, mES, mouse embryonic stem cells;
HSC, mouse hematopoietic stem cells; hybrids,
mouse HSC/ES cell hybrids, iPS, mouse induced
pluripotent stem cells.
14
IZKF Aachen Progress Report 2011
Project Funding
|
Medicine and Technology
| T2
2.1.
Funding period: 01.07.2008 - 30.06.2011
Staff: TV-L 9 (Brosig S.)
Materials 2011: € 3,400
Investments/Equipment 2011: –
as cell adhesion, morphology, vitality, cytotoxicity and apoptosis, were investigated (Figure 1).
Polymers were then analyzed whether they supported feeder-free growth of pluripotent stem
cells. Indeed, we identified polymers maintaining
feeder-free growth for at least 11 days. Next, we
analyzed stem cell differentiation on polymers
and identified biopolymers that supported and/
or enhanced cardiomyogenic differentiation.
For example, germline derived pluripotent stem
cells (gPS cells) cultured on a specific Resomer
showed an enhanced expression of cardiomyogenic genes and a higher frequency of beating
areas than control.
The project was performed in cooperation with
J. Groll and M. Möller (Institute for Textile and
Macromolecular Chemistry, RWTH Aachen University, Aachen, Germany) and with K. Ko, J. B.
Kim and H. R. Schöler (Max-Planck-Institute for
Molecular Biomedicine, Münster, Germany).
Publications
IZKF relevant, project associated
1. Ding, X., Lin, Q., Ensenat-Waser, R., RoseJohn, S. and Zenke, M. (2011). Polycomb
group protein Bmi1 promotes hematopoietic
cell development from ES cells. Stem Cells
Dev. 21, 121-132. [IF 4.791]
2. Hoss, M., Apel, C., Dhanasingh, A., Suschek,
C. V., Hemmrich, K., Salber, J., Zenke, M. and
Neuss, S. (2011). Integrin alpha4 impacts on
differential adhesion of preadipocytes and
stem cells on synthetic polymers. J. Tissue
Eng. Reg. Med., in press. [IF 3.86]
3. Ko, K., Reinhardt, P., Tapia, N., Schneider, R.
K., Araúzo-Bravo, M. J., Han, D. W., Greber,
B., Kim, J., Kliesch, S., Zenke, M. and Schöler,
H. R. (2011). Evaluating the potential of putative pluripotent cells derived from human testis. Stem Cells 29, 1304-1309. [IF 7.871]
4. Müller, M., Stockmann, M., Malan, D., Wolheim, A., Tischendorf, M., Linta, L., Katz, S.F., Lin, Q., Latz, S., Brunner, C., Wobus, A.
M., Zenke, M., Wartenberg, M., Böckers, T.
M., von Wichert, G., Fleischmann, B., Liebau,
S. and Kleger, A. (2011). Ca2+-activated K+channels - New tools to induce cardiac commitment from pluripotent stem cells in mice
and men. Stem Cell Rev. and Rep., in press.
[IF 3.766]
5. Neuss, S., Denecke, B., Gan, L., Lin, Q., Bovi,
M., Apel, C., Wöltfe, M., Dhanasingh. A., Salber, J., Knüchel, R. and Zenke, M. (2011).
Transcriptome analysis of MSC and MSC-derived osteoblasts on Resomer LT706 and PCL:
Impact of biomaterial substrate on osteogenic
differentiation. PLoS ONE, e23195. [IF 4.411]
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Zenke, M.
Reprogramming and somatic memory
in ES cell/hematopoietic cell hybrids
DFG Ze 432/51/2
04/200806/2014
€ 518,800
Zenke, M.
Reprogramming of and programming
by mesenchymal stem cells (MSC)
DFG Ze 432/6-1
11/201010/2013
€ 195,000
Zenke, M.
Wagner, W.
StemCellFactory: Automatic production, EU/Bio.NRW
expansion and differentiation of induce
pluripotent stem cells (iPS cells)
11/201010/2013
Total
volume
€ 5.26 M
€ 441,000
Neuss-Stein, S.
Hieronymus, T.
Zenke, M.
Biomaterial scaffolds for CB-HSC
expansion
03/200912/2012
€ 259,500
BMBF
IZKF Aachen Progress Report 2011
15
2.1.
Project Funding
|
Medicine and Technology
| T2
Neuss-Stein, S.
In vivo recruitment of mesenchymal
stem cells by growth factor-loaded
biomaterials for enhancing tissue
regeneration
04/201103/2014
€ 400,000
Neuss-Stein, S.
Textile medical products of biomimetic EU/Hightec.NRW 06/2011silk with integrated bioactive com05/2013
pounds for treatment of chronical sores
€ 133,242
DFG
Promoting of young researcher
Doctoral Theses
16
Hoß, M.
Ongoing
RWTH Aachen,
Faculty 1
Germline-derived pluripotent stem cells for tissue
engineering
Qin, J.
Ongoing
RWTH Aachen,
Faculty 1
Towards enhancing the differentiation potential of
human iPS cells
IZKF Aachen Progress Report 2011
Project Funding
|
Medicine and Technology
| T3
2.1.
Funding period: 01.07.2008 - 30.06.2011
Staff: TV-L 9 (Kong Y.)
Materials 2011: € 5,800
Investments/Equipment 2011: –
Plasmacytoid dendritic cells and plaque instability
Günther E. (Institute for Molecular Cardiovascular Research)
This study focuses on the understanding of the
pathophysiological role of neutrophils and plasmacytoid dendritic cells in atherosclerosis.
Atherosclerosis is now agreed to be a chronic inflammatory disease of the vessel wall driven by
intense immunological activity of both innate and
adaptive immunity. Whereas monocytes/macrophages are of paramount importance, polymorphonuclear neutrophilic leukocytes (PMN) have
recently also been implicated in lesion formation.
Given the expansion of these cell types in myeloproliferative disease, we investigated atherosclerotic lesion formation in Interferon regulatory
factor 8-deficient (Irf8-/-) mice here. The chronic
myelogenous leukemia (CML)-like phenotype
with expanded PMN but reduced frequencies
of monocytes in bone marrow and peripheral
blood in atherosclerosis-prone apolipoprotein
E-deficient (Apoe-/-) mice reconstituted with Irf8/bone marrow was associated with an increased
lesional accumulation of PMN, apoptotic cells, a
more pro-inflammatory plaque phenotype, and
exacerbated atherosclerotic lesion formation
in comparison to Irf8+/+ bone marrow-recipient
Apoe-/- mice. Although accumulating in equal numbers at sites of inflammation and plaque growth,
Irf8-/- macrophages were defective in phagocytosis of apoptotic cells and lipids as well as cytokine production, contrasting unaffected reactive
oxygen species formation, and discharge of PMN
granule components by Irf8-/- compared to IRF8+/+
PMN. Depletion of PMN in atherosclerotic mice
reconstituted with Irf8-/- bone marrow abrogated
increased lesion formation. These data indicate
that the expansion of functionally intact PMN in
ill alliance with impaired macrophage functions
critically contribute to atherosclerosis and imply
that long-standing CML-syndromes may associate with enhanced atherosclerosis.
Dendritic cells are a very heterogenous group of
antigen presenting cells and their role in atherosclerotic lesion formation is not clear. Even less is
known about plasmacytoid dendritic cells (pDCs)
in this context. Thus, this study wanted to unravel the role of pDC in atherosclerosis. Besides
the detection of murine pDCs in atherosclerotic
lesions, it could be further demonstrated, that
specific pDC activation significantly aggravates
atherosclerotic lesion formation, while depletion
of pDCs decreases early plaque development.
Furthermore, pre-treatment of pDCs with oxLDL
increases their antigen uptake capacity, leading
to enhanced antigen specific T cell proliferation in
vivo. Notably, not only oxLDL stimulation of pDCs,
but also mechanisms accounting for breakdown
of immune tolerance resulting in pDC activation
in autoimmune diseases, could be identified for
atherosclerosis. Cramp-self-DNA complexes
stimulated IFN-alpha secretion by pDCs in vitro,
while Cramp-/- Ldlr-/- mice displayed reduced
plaque formation. In contrast, Apoe-/- mice stimulated with Cramp exhibited enlarged atherosclerotic lesion development. In addition, exacerbated plaque formation was always accompanied by
increased anti-ds-DNA antibody serum titers and
stimulation of pDCs with high anti-ds-DNA sera in
vitro induced IFN-alpha secretion. Thus, chronic
stimulation of pDCs by modified lipoproteins and
autoimmune mechanisms may critically drive inflammation in atherosclerosis.
Publications
IZKF relevant, project associated
1. Döring, Y.*, Soehnlein, O.*, Drechsler, M., Meiler, S., Shagdarsuren, E., Hartwig, H., Hieronymus, T., Hristov, M., Koenen, R.R., Zenke, M.,
Weber, C., and Zernecke, A., Chronic myelog-
enous leukemia-like disease due to hematopoietic IRF8-deficiency fuels atherosclerosis in
mice. Circulation Research, 2011 (in revision).
IZKF Aachen Progress Report 2011
17
2.1.
Project Funding
|
Medicine and Technology
| T3
2. Döring, Y., Manthey, H., Drechsler, M.,
Lievens, D., Manca, M., Hartwig, H., Busch,
M., Koenen, R.R., Soehnlein, O., Zenke, M.,
Daemen, M.J., Weber, C., Lutgens, E., and
Zernecke, A., Autoantigenic protein-DNA complexes stimulate plasmacytoid dendritic cells
to promote atherosclerosis. Nature Medicine,
2011 (under review).
Promoting of young researcher
Doctoral Theses
Döring, Y.
18
2011
IZKF Aachen Progress Report 2011
RWTH Aachen,
Faculty 1
Plasmacytoid dendritic cells and neurophils
underestimated cells populations during the onset
of atherosclerosis
Project Funding
|
Medicine and Technology
| T4
2.1.
Funding period: 01.07.2008 - 30.06.2011
Staff: ½ TV-L 9 (Winkler S.)
Materials 2011: € 15,400
Investments/Equipment 2011: –
Role of platelets and platelet-derived chemokines in the
recruitment of dendritic cells
Noels H. (Institute for Molecular Cardiovascular Research)
Monocytes and dendritic cells (DCs) play an important role in the development and progression
of atherosclerosis. It is therefore important to
unravel the mechanisms underlying their recruitment into the vessel wall, as this could offer new
options for future therapeutic strategies. Thrombocytes are involved in leukocyte adhesion to
the vessel wall, mainly through secretion of chemokines that work synergistically through the
formation of chemokine-heterodimers. The aim
of this project is to unravel the role of platelets
and platelet-derived chemokines in the recruitment of DCs. First, the isolation of plasmacytoid
DCs (pDCs) from human blood was optimized
Figure 1: Quantification of pDC chemotaxis through flow cytometric analysis.
IZKF Aachen Progress Report 2011
19
2.1.
Project Funding
|
| T4
Medicine and Technology
and the isolated cells were characterized through
flow cytometric analysis of pDC surface markers (CD11c, BDCA-1, BDCA-2, BDCA-4). Next,
the pDCs were stimulated with the thrombocytic
chemokines CCL5 and CXCL4, and the mRNA
expression of a multitude of chemokines and
chemokine receptors was quantified through
real-time quantitative PCR using the „PCR Array
RT2 ProfilerTM PCR Array Chemokines and Receptors“ from SA Biosciences. Interestingly, an
increased expression of CCR3, CCR7 and CCR5
was observed in stimulated versus unstimulated
pDCs. To examine the effect of modified chemokine receptor expression on pDC recruitment, in
vitro chemotaxis assays need to be performed.
As a proof of principle and to optimize the chemotaxis protocol, we investigated human pDC
recruitment to the chemokine CXCL10. CXCL10
is a ligand for the chemokine receptor CXCR3,
known to be expressed on pDCs and to mediate
pDC recruitment. As shown in Figure 1, human
pDCs were quantified in human peripheral blood
mononuclear cell (PBMC) preparations by flow
cytometric analysis of the pDC markers BDCA-2
and BDCA-4 before chemotaxis, and after chemotaxis triggered by the chemokine CXCL10. In
future, chemotaxis of unstimulated and stimulated pDCs towards diverse chemokines will be
quantified in similar assays.
Publications
IZKF relevant, project associated
1. Sarabi A, Kramp BK, Drechsler M, Hackeng
TM, Soehnlein O, Weber C, Koenen RR, Von
Hundelshausen P. (2011) CXCL4L1 inhibits
angiogenesis and induces undirected endo-
thelial cell migration without affecting endothelial cell proliferation and monocyte recruitment.
J Thromb Haemost. 9:209-219. [IF 5.439]
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
von
Hundelshausen,
P.
Thrombocytic chemokines in
atherosclerosis
DFG/Hu 1618/1-2 01/201112/2013
€ 600.000
Promoting of young researcher
Doctoral Theses
Sarabi, A
20
2011
IZKF Aachen Progress Report 2011
RWTH Aachen,
Biology
Structural and functional characterization of the interactions of the platelet-derived chemokines CCL5,
CXCL4 and CXCL4L1
Project Funding
|
Medicine and Technology
| T5
2.1.
Funding period: 01.07.2008 - 30.06.2011
Staff: ½ TV-L 9 (Winkler S.)
Materials 2011: € 15,400
Investments/Equipment 2011: –
Imaging and role of Junctional Adhesion Molecule (JAM) A
in atherogenic pathogenesis
Noels H. (Institute for Molecular Cardiovascular Research)
The recruitment of inflammatory leukocytes into
the vessel wall is a crucial step in the development and progression of atherosclerosis, and is
mediated by adhesion molecules presented on
the endothelial cell layer of the vessel wall. The
junctional adhesion molecule A (JAM-A) is localized in the intercellular junctions of endothelial
cells and regulates the permeability of the endothelial cell layer. However, inflammatory conditions can induce a relocalization of JAM-A to the
apical side of endothelial cells, triggering JAMA-mediated leukocyte recruitment. This project
aims to examine the expression, dynamics and
function of JAM-A in the context of atherosclerosis.
With the help of two-photon laser scanning microscopy, we were able to show that JAM-A is localized in the CD31+ endothelial cell contacts of a
carotid artery of a healthy mouse. Similar results
were obtained in a healthy part of the common
carotid artery of an atherosclerotic ApoE-/- mouse
(Fig. 1A). However, a significant reorganization of
JAM-A was detected under proatherogenic conditions, showing a JAM-A redistribution to the luminal site of endothelial cells in the plaque-prone
bifurcation of a carotid artery from an atherosclerotic ApoE-/- mouse (Fig. 1B). Semi-quantitative
evaluation of the colocalization of JAM-A and
CD31, as expressed by the Mander’s Colocalization Coefficient (MCC), confirms a decreased colocalization in plaque-prone regions of the carotid
artery in mice (Fig.1C, n=6).
We could validate our findings with an in vitro
assay, showing a relocalization of JAM-A to the
apical side of human aortic endothelial cells after
treatment with oxidized LDL. This was associated
with an increased JAM-A-mediated monocyte
transmigration in vitro, indicating that the JAM-A
reorganization makes JAM-A more available for
leukocytes, causing an increased adherence and
transmigration rate. Thus, our data indicate that
this JAM-A reorganization could facilitate and accelerate atherogenesis.
Figure 1: Redistribution of JAM-A under atherogenic conditions.
IZKF Aachen Progress Report 2011
21
2.1.
Project Funding
|
| T5
Medicine and Technology
Publications
IZKF relevant, project associated
1. Vasina EM, Cauwenberghs S, Feijge MA,
Heemskerk JW, Weber C, Koenen RR. (2011)
Microparticles from apoptotic platelets promote resident macrophage differentiation. Cell
Death Dis. 2:e210 [IF due for 2012]
2. Kanzler I, Liehn EA, Koenen RR, Weber C
(2011) Anti-Inflammatory therapeutic approaches to reduce acute atherosclerotic
complications. Curr Pharm Biotechnol. Apr 6.
[Epub ahead of print] [IF 3.455]
3. Kramp BK, Sarabi A, Koenen RR, Weber C
(2011) Heterophilic chemokine receptor inter-
actions in chemokine signaling and biology.
Exp Cell Res. 317:655-663. [IF 3.609]
4. Sarabi A, Kramp BK, Drechsler M, Hackeng
TM, Soehnlein O, Weber C, Koenen RR, Von
Hundelshausen P. (2011) CXCL4L1 inhibits
angiogenesis and induces undirected endothelial cell migration without affecting endothelial cell proliferation and monocyte recruitment.
J Thromb Haemost. 9:209-219. [IF 5.439]
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Koenen, R.R.
Fraemohs, L.
Weber, C.
Characterization of alternative LFA-1
ligands by inflammatory and atherogenic cell recruitment
DFG 2948/1-2
01/201101/2014
€ 220,000
Promoting of young researcher
Doctoral Theses
Schmitt, M.
22
Ongoing
IZKF Aachen Progress Report 2011
RWTH Aachen,
Biology
Role and dynamics of JAM-A in atherogenic
inflammation
Project Funding
|
Medicine and Technology
| T6
2.1.
Funding period: 01.07.2008 - 31.12.2011
Staff: ½ TV-L 13 (Diamantouros S.)
Materials 2011: € 5,950
Investments/Equipment 2011: –
The Vital Stent – Novel Composite Structure of Self-Expanding
Stent & Tissue Engineered Vessel
Jockenhövel S. (AME - Institute of Applied Medical Engineering,
Dept. of Tissue Engineering & Textile Implants, Helmholtz Institute Aachen)
Gries T. (Institute of Textile Technology)
Mahnken A. (Department of Diagnostic and Interventional Radiology)
Despite great advances in medicine and numerous different stents available, re-stenoses are
still a important problem. The solution might be a
stent with a protective autologous tissue surface.
In previous years the fibrin-based principle of tissue engineering in the cardiovascular field has
been studied and has been applied on the Vitalstent. Suitable cells have been investigated and
the mould was optimized. Furthermore the stent
structure, coating and the crimp performance
have been evaluated and optimized. A stent
structure, adapted on the needs, has been devel-
oped and the coating was modified accordingly.
Due to promising results of in vitro studies (Fig.
1 A+B) the tissue engineered stent was tested in
vivo for the first time. For this reason, cells were
isolated from sheep, cultivated and seeded in the
tissue engineered stent construct. The resulting
vitalized stents were then implanted in the carotid
artery of the corresponding sheep. A commercial
stent was implanted at the contralateral side, as
control. The correct position and function of the
stent was proven by angiography (Fig. 1 C).
Figure 1: VitalStent:. The stent showed an intact coating (A) and the immunostaining proves a vital tissue (red = alpha smooth
muscle actin, blue = nucleus) (B), VitalStent in A. carotis (C)
Publications
IZKF relevant, project associated
1. Weinandy S, Rongen L, Schreiber F, Cornelissen C, Flanagan TC, Mahnken AH, Gries T,
Schmitz-Rode T, Jockenhoevel S. (2011) The
BioStent – Novel
Concept for a Viable Stent Structure. Tissue Eng.
Part A (accepted with revision, revision submitted) [IF 4.636]
2. Soehnlein O, Wantha S, Simsekyilmaz S,
IZKF Aachen Progress Report 2011
23
2.1.
Project Funding
|
| T6
Medicine and Technology
Döring Y, Megens RT, Mause SF, Drechsler M,
Smeets R, Weinandy S, Schreiber F, Gries T,
Jockenhoevel S, Möller M, Vijayan S, van Zandvoort MA, Agerberth B, Pham CT, Gallo RL,
Hackeng TM, Liehn EA, Zernecke A, Klee D,
Weber C. Neutrophil-derived cathelicidin protects from neointimal hyperplasia. Sci Transl
Med. 2011 Oct 5; 3(103):103ra98. [IF 3.292]
3. Bach, C.; Jockenhövel, S.; Gries, T. Produkt-,
Prozess- und Maschinenentwicklung in der
textilen Medizintechnik Tec2: das TechnikMagazin von Landesverband NRW des VDI,
Aachener und Kölner BV 126 (2011), H. 4, S.
22-23
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Weber, C.
Möller, M.
Cell Adhesion at Vascular Interfaces
DFG/RWTH
07/2009Exzellenzinitiative 07/2012
MTBo07
AG
Jockenhövel
€ 84,305
Kiesling, F.
Patient customized engineering
for smart cardiovascular therapy –
development & imaging of
patient-customized implants
Ziel2.NRW
InnoMet EU/
Land NRW
07/201007/2013
€ 4.484.492
thereof AG
Jockenhövel
€ 395,780
Jockenhövel, S.
PULMOSTENT Development &
Evaluation of a Viable Stent Device
for the Treatment of Broncho
Tracheal Cancer
EU-FP7 20112014
NMP-2011-2.2-2
20112014
€ 3.895.000
thereof AG
Jockenhövel
€ 656,000
Univ. of Limerick
(Coordinator)
ANTI-MICROBIAL STENT A
Clean-on–Demand, Biofilm-resistant
Indwelling Device (CODID)
EU-FP7 20112014
HEALTH.
2011.2.3.1-5
applied
€ 4.254.000
thereof AG
Jockenhövel,
Tolba
€ 432,000
Jockenhövel, S.
Promoting of young researcher
Diploma Theses
Peusquens, J.
Ongoing
University Bonn
Evaluation of the fate of endothelial cells on hydrogels for the vascular grafts and BioStent cell lining
Ongoing
RWTH Aachen
In vitro and in vivo evaluation of the BioStent
Doctoral Theses
Rongen, L.
Awards
Young Researcher Award 2011, European Symposium of Vascular Biomaterials, Stefan Weinandy
(AME - Institute of Applied Medical Engineering Helmholtz Institute Aachen)
24
IZKF Aachen Progress Report 2011
Project Funding
|
| T6
2.1.
IZKF Aachen Progress Report 2011
25
Medicine and Technology
Patents and patent applications
PCT/DE 2010/001506 Deutschland – Stent mit biologischem Gel – BioStent
Title:
Stent mit biologischem Gel - BioStent
Patent applicants:
S. Jockenhövel, T. Deichmann, T. Schmitz-Rode, T. Gries, A. Mahnken,
S. Weinandy
Date of application: 22.12.2010
Patent office:
Deutsches Patent- und Markenamt
Patent number:
DE10 2009 060 5460
2.1.
Project Funding
|
Medicine and Technology
| T7
Labelling of Stem Cells and Immune Cells with Functionalized
Iron-Oxide Nanoparticles for in vivo Cell Tracking
Zenke M. (Institute of Biomedical Engineering - Cell Biology)
Cellular therapies using stem cells and immune
cells are at the focus of extensive research and
are increasingly applied in clinical trials. Accurate
delivery and functional integration of these cells
into target organs remain essential for the success of such therapies. However, the ability to
non-invasively monitor cell trafficking, cell deposition or a specific cellular function at the target site
after application is rather limited. Molecular imaging using magnetic resonance imaging (MRI)
offers the means to non-invasively (i) monitor
transplanted cells within their anatomical context
and (ii) provide information about their functional
status when used in combination with engineered
magnetic nanoparticles (MNPs).
In this project, we investigated the uptake of
chemically engineered nanoparticles into antigen presenting dendritic cells (DCs). DCs are
expected to perceive MNPs as foreign antigens,
thus exhibiting the capability to immunologically
sense MNP surface chemistry. In order to systematically evaluate cellular uptake and T2/T2*
MR imaging properties of MNPs, we synthesized
polymer-based MNPs by employing layer-bylayer (LbL) technology (in collaboration with W.
Richtering, Institute of Physical Chemistry (IPC),
Figure 1: Polyelectrolyte coating of magnetic nanoparticles (MNPs) using the layer-by-layer technique allows specific tailoring
of MNP surface attributes, such as charge, particle size and shell chemistry. (a) Polyelectrolyte-coated MNPs represent effective cell labelling agents for DCs but differ in uptake and sub-cellular packaging that impact on MRI contrast properties. (b)
Uptake efficiency of MNPs determined by magnetic separation. (c) Intracellular iron concentration in MNP-labeled cells.
26
IZKF Aachen Progress Report 2011
Project Funding
|
Medicine and Technology
| T7
2.1.
Funding period: 01.07.2009 - 30.06.2011
Staff: ½ TV-L 9 (Mertens N.)
½ SHK (Grego A., Wolf D.,
Klisch T., Thönes S.)
Materials 2011: € 5.350
Investments/Equipment 2011: –
RWTH Aachen, University Aachen, Germany).
Thereby, we achieved modification of particle
shell parameters, such as size, surface charge
and chemistry. We found that sub-cellular packaging of MNPs rather than MNP content in DCs
influences MR imaging quality. Increased local
intracellular electron density, as inferred from
transmission electron microscopy, strongly correlated with enhanced contrast in MRI (in collaboration with F. Kiessling, Institute for Biomedical
Engineering – Experimental Molecular Imaging,
RWTH Aachen University, Aachen, Germany; U.
Himmelreich and M. Hodenius, Biomedical NMR
Unit/MoSAIC, Faculty of Biomedical Sciences
and Laboratory of BioNanoColloids, Interdisciplinary Research Centre, Katholic University Leuven, Belgium; M. Hoehn, In vivo NMR Research
Group, MPI for Neurological Research, Cologne,
Germany). Thus, LbL-tailoring of MNP shells using polyelectrolytes, which impact on uptake and
sub-cellular localization, can be used for modulating MR imaging properties.
Publications
IZKF relevant, project associated
1. Schwarz, S., Wong, J. E., Bornemann, J.,
Hodenius, M., Himmelreich, U., Richtering,
W., Hoehn, M., Zenke, M. and Hieronymus,
T. (2011). Polyelectrolyte coating of iron ox-
ide nanoparticles for MRI-based cell tracking. Nanomedicine, in press, http://dx.doi.
org/10.1016/j.nano.2011.08.010. [IF 4.882]
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Japan Society
09/2010for the Promotion 02/2011
of Science,
Pre-doctoral
fellowship
€ 17,500
Schwarz, S.
The impact of TLRs and TLR signaling
pathways on the interaction of
magnetic nanoparticles with dendritic
cell functions
(in collaboration with S. Akira,
Universität Osaka, Japan)
Zenke, M.
TGF-beta/Id2 signalling in development DFG/SFB 542
of antigen presenting dendritic cells
B10
07/200806/2011
€ 377,100
Neuss-Stein, S.
Hieronymus, T.
Zenke, M.
Biomaterial scaffolds for CB-HSC
expansion
BMBF
03/200912/2012
€ 259,500
Zernecke, A.
Zenke, M.
Jung, S.
Vascular dendritic cells in
atherosclerosis
DFG/FOR809
ZE 827/1-2
03/201002/2013
€ 280,000
Promoting of young researcher
Doctoral Theses
Schwarz, S.
Ongoing
RWTH Aachen,
Faculty 1
Magnetic resonance imaging (MRI) with engineered
nanoparticles
IZKF Aachen Progress Report 2011
27
2.1.
Project Funding
|
Medicine and Technology
| T8
Combination of OCT and NIRF-OT for improving diagnosis
in carcinoma
Kiessling F. (Department of Experimental Molecular Imaging)
One important criterion for the discrimination
between pre-invasive and invasive tumor stages
in bladder and skin lesions is the integrity of the
basement membrane. At the invasive stage, the
basement membrane is degraded by matrix metalloproteinases (MMP). Alternatively to invasive
biopsies, optical coherence tomography (OCT)
can deliver morphological information of the
basement membrane status, whereas near-infrared-functional optical tomography (NIRF-OT)
allows the assessment of active MMPs in vivo.
Thus, combining OCT and NIRF-OT will be an
important step for non-invasive tumor diagnosis.
Due to undetectable MMP activity in human blad-
der carcinoma samples, the model was shifted
to the HaCaT model of skin carcinogenesis with
a tumor-stage dependent MMP-activity. For
characterizing the aggressiveness of different
carcinoma types, the highly invasive HaCaT-ras
A5-RT3 cells were injected subcutaneously (s.c.)
and intradermally (i.d.). A specialized multi-dimensional OCT system was developed to image
the samples.
A higher MMP-activity was detected in s.c. than
i.d. tumors which was confirmed by immunohistochemistry. Analysis of the basement membrane
status by OCT was very difficult due to the geometrical properties as well as the high scattering
Figure 1: A: MMP-Activity in i.d. vs.
s.c. tumors. B: Nanoparticles tested
in OCT as contrast agents.
28
IZKF Aachen Progress Report 2011
Project Funding
|
Medicine and Technology
| T8
2.1.
Funding period: 01.07.2009 - 30.06.2011
Staff: ½ TV-L 13 (Al Rawashdeh W.)
½ TV-L 9 (Labude N.)
½ TV-L 13 (Oya Kray)
Materials 2011: € 9,000
Investments/Equipment 2011: –
and absorption coefficients of skin and the tumor,
resulting in a limited penetration depth for OCT
measurements. Further studies are directed to
monitor MMP-activity by NIRF-OT at different
tumor stages and to visualize the tumor border
zone by OCT.
Since a direct combination of both modalities will
facilitate the analyses, we additionally focused
on bimodal contrast agents. Various particles
were tested for their scattering properties in OCT
in phantoms. Polystyrene particles generated a
markedly higher OCT backscattering signal compared with nanogels and gold nanoparticles, thus
showing the highest potential as a dual-modality
contrast agent. Selected particles will be tested
for dual-modality imaging after coupling of an
NIRF-dye.
Publications
IZKF relevant, project associated
1. Kray, Lenz, Spöler, and Kurz, Increased tissue
contrast by high-resolution simultaneous dualband optical coherence tomography in three
dimensions, Proc. SPIE 8092, 809209 (2011).
2. Kray, Lenz, Spöler, Kray, Schrage, and Kurz,
Pathogenesis oft he dry eye syndrome observed by optical coherence tomography in
vitro, Proc. SPIE 8091, 809126 (2011).
Promoting of young researcher
Diploma Theses
Lenz, M.
2011
RWTH Aachen,
Faculty of
Electrical
Engineering
Ultra-high resolution three-dimensional optical
coherence tomography for the analysis of dynamic
processes
Al
Ongoing
Rawashdeh, W.
RWTH Aachen,
Medical Faculty
Combination of Optical Coherence Tomography
(OCT) and Near-InfraRed-Functional Optical
Tomography (NIRF-OT) for improving diagnosis
in carcinoma
Kray, S.
RWTH Aachen,
Faculty of
Electrical
Engineering
Novel non-mechanical detection schemes for optical
coherence tomography
Doctoral Theses
2011
IZKF Aachen Progress Report 2011
29
2.1.
Project Funding
|
Medicine and Technology
| T9
Mechanobiology
Fischer H. (Dental Materials and Biomaterials Research)
The microstructure and chemical composition of
bone change during the course of years. Therefore,
bone replacement for elderly people still causes
many issues. In the project T9 the Department of
Dental Materials and Biomaterials Research, the
Institute of Pathology / IBMT-Biointerface and the
Department of Anatomy and Cell Biology are working in close cooperation to
identify prerequisite conditions for bioresorbable bone
implants for older patients.
In 2011, the Department of
Dental Materials and Biomaterials Research started the
project with the structural
and chemical analysis of human aged bone. Macerated
vertebrae bone was delivered from the Department
of Molecular and Cellular
Anatomy. Computer tomogFigure 1: Virtual model of a sagittal raphy measurements were
vertebrae bone plate, scanned by —- performed and virtual 3D
CT.
models were generated. A
structural density of 20 % with a local density distribution between 11 % and 41 % within the vertebrae
bone was calculated. X-ray diffraction and x-ray
fluorescence analysis revealed a bone composition of hydroxyapatite with traces of magnesium,
iron, sulphur and silicon. Highly pure ß-tricalcium
phosphate and hydroxyapatite were synthesized
using wet chemical reactions and heat treatments.
In cooperation with PD Dr. Sabine Neuss-Stein
(Institute of Pathology and IBMT-Biointerface),
cytotoxicity tests with L929 mouse fibroblasts
and mesenchymal stem cells were performed on
ß-tricalcium phosphate specimens with a special
focus on surface properties and sinter grade. Prof.
Pufe (Department of Anatomy and Cell Biology)
has written a proposal for the Ethics Committee for
an osteoporotic mouse model. First test implants
out of ß-tricalcium phosphate were manufactured
at the Department of Dental Materials and Biomaterials Research to determine, if small geometries
for the bones of mice could be generated. In the
future the scaffolds will also be improved by incorporation of a defined porosity. In this context a new
3D wax-printer (T76+, Horbach, Idar-Oberstein)
that was purchased by the Department of Dental
Materials and Biomaterials Research for a running
BMBF project in the beginning of 2012 could also
be helpful for this IZKF project. With it, customized
scaffolds with an interconnected porosity can be
generated.
Publications
IZKF relevant, project associated
1. Lichte P, Pape HC, Pufe T, Kobbe P, Fischer H
(2011). Scaffolds for bone healing: Con¬cepts,
Materials and Evidence. Injury 42:569-573.
2. Neuss S, Denecke B, Gan L, Lin Q, Bovi M,
Apel C, Wöltje M, Dhanasingh A, Salber J,
30
IZKF Aachen Progress Report 2011
Knüchel R, Zenke M (2011) Transcriptome
analysis of MSC and MSC-derived osteoblasts
on Resomer® LT706 and PCL: impact of biomaterial substrate on osteogenic differentiation. PLoS One 6(9):e23195.
Project Funding
|
Medicine and Technology
| T9
2.1.
Materials/Travel expenses 2011: € 21,300
Investments/Equipment 2011: –
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Fischer, H.
BioMin I+II: Functionalized mineral
BMBF/ 3G0712A 07/2008surfaces: Sorption mechanisms of
02/2012
growth stimulating proteins on surfaces
of calcium phosphate based bone
substitute materials
Entire project:
€ 840,000
Own share:
€ 240,000
Fischer, H.
DigImprint - Development of a
three-dimensional sensor for digital
intraoral recording of dental
preparations (in vivo), for the
manufacturing of dental restorations
with improved design
BMBF/ 13N9658 03/200912/2011
Entire project:
€ 1.5 M
Own share:
€ 325,000
Fischer, H.
MimeticBone – Development of a
graded resorbable implant for the
medical treatment of long-bone
segmental defects
Winner project of the BMBF“Innovation Competition of Medical
Technology 2010“
BMBF/
01EZ1109A
07/201112/2013
Entire project:
€ 400,000
Own share:
€ 215,000
Fischer, H.
BioLot - Functionalization of inert
high performance ceramic materials
by deposition of bioactive braze
DFG/
FI 975/16-1
02/201201/2014
Entire project:
€ 380,000
Own share:
€ 190,000
Neuss-Stein, S. Biomaterial scaffolds for CB-HSC
Hieronymus, Th. expansion
Zenke, M.
BMBF
03/2009 € 259,500
–02/2012
Neuss-Stein, S. In vivo recruitment of mesenchymal
stem cells via growth facto-loaded
biomaterials for enhanced tissue
regeneration
DFG
04/201103/2014
€ 400,000
Neuss-Stein, S. Textile medical products derived from
biomimetic silk with integrated factors
for the treatment of cronical wounds
Hightec.NRW
(BMBF Call)
06/201105/2013
€ 133,242
Pufe, T.
DFG
PU 214/3-2
-07.2012
€ 325,000
The role of VEGF in Osteoarthritis
IZKF Aachen Progress Report 2011
31
2.1.
Project Funding
|
Medicine and Technology
| T9
Promoting of young researcher
Diploma Theses
Duffy, M.P.
2011
RWTH Aachen, Faculty
Matrix-based bone substitutes using
of Medicine (Biomedical
mesenchymal stem cells
Engineering), Department of
Dental Materials and Biomaterials Research (ZWBF)
Houben, A.
2011
RWTH Aachen,
Biology
The expression of VEGF in chondrocytes
due to mechanical forces
Ongoing
RWTH Aachen, Institute of
Pathology and IBMTBiointerface in cooperation
with the Animal Facility
Matrix-based bone substitutes using
mesenchymal stem cells
Doctoral Theses
Adamzyk, C.
Awards
Sabine Neuss-Stein received the Friedrich-Wilhelm-Preis 2011 of RWTH Aachen for her „Habilitationsschrift“
entitled “Mesenchymal stem cells and their interactions with biomaterials for tissue engineering applications“
32
IZKF Aachen Progress Report 2011
Project Funding
|
Medicine and Technology
| T9-1
2.1.
Staff: TV-L 13 (Bergmann C.)
SHK (Dornebusch H.)
Materials/Travel expenses 2011: € 7,900
Investments/Equipment 2011: –
Development of tailored mineral 3D scaffolds for suitable
treatment of bone defects of elderly patients
Fischer H. (Dental Materials and Biomaterials Research)
The project goals in the year 2011 were the micro-structural and chemical analysis of human
bone tissue of elderly people. Human bone tissue undergoes structural alterations and chemical changes during the course of years. It is
necessary to better understand these changes
for the development of customized implants for
the elderly.
Computer tomography measurements were used
for the analysis of the micro-structure. Dorsal vertebrae (L4, L5) were macerated and a 5 mm plate
was sawed out of the vertebral body, parallel to
the sagittal plane. These plates were scanned by
computer tomography with a resolution of 20 —m.
The CT data were converted into virtual 3D models and the density of the bone was calculated
from them. The first results showed an overall
density of approx. 20 %, while the density within
the bone plate varied between 11 % and 41 %.
The elemental composition of the bones was
determined by x-ray fluorescence analysis. As
expected the main elements were calcium (60.5
wt.-%) and phosphor (38.1 wt.-%). Traces of
magnesium, iron, sulphur and silicon were also
found.
The phase composition was analyzed by x-ray
powder diffraction of macerated bone material
before and after a calcination process. After the
heat treatment a calcium deficient hydroxyapatit
with a calcium deficiency of 2.4 % was determined. Due to a higher x-ray scattering, this exact
determination was not possible with the uncalcinated bone material.
Although it was not part of the project goals for
2011 but rather 2012, the synthesis of highly pure
hydroxyapatite and ß-tricalcium phosphate was
started. Based on calcium carbonate and phosphorus acid a process was developed including
wet milling, spray drying and heat treatment. It
was possible to synthesise
hydroxyapatite and ß-tricalcium phosphate at temperatures between 800 °C
and 1000 °C. Moreover, a
3D wax-printer (T76+, Horbach, Idar-Oberstein) was
purchased, for running a
BMBF-project for the fabrication of bone replacement
scaffolds with a customized
and interconnected porosity. This 3D wax printer
could also be useful for this
IZKF project.
Figure 1: Virtual model of a sagittal vertebrae bone plate, scanned
by —-CT.
IZKF Aachen Progress Report 2011
33
2.1.
Project Funding
|
| T9-1
Medicine and Technology
Publications
IZKF relevant, project associated
1. Lichte P, Pape HC, Pufe T, Kobbe P, Fischer H (2011). Scaffolds for bone healing: Concepts, Materials
and Evidence. Injury 42:569-573.
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Fischer, H.
BioMin I+II: Functionalized mineral
surfaces: Sorption mechanisms of
growth stimulating proteins on
surfaces of calcium phosphate based
bone substitute materials
BMBF/ 3G0712A 07/200802/2012
Entire project:
€ 840,000
Own share:
€ 240,000
Fischer, H.
DigImprint - Development of a
three-dimensional sensor for digital
intraoral recording of dental
preparations (in vivo), for the
manufacturing of dental restorations
with improved design
BMBF/13N9658
03/200912/2011
Entire project:
€ 1.5 M
Own share:
€ 325,000
Fischer, H.
MimeticBone – Development of a
graded resorbable implant for the
medical treatment of long-bone
segmental defects
Winner project of the BMBF“Innovation Competition of Medical
Technology 2010“
BMBF/
01EZ1109A
07/201112/2013
Entire project:
€ 400,000
Own share:
€ 215,000
Fischer, H.
BioLot - Functionalization of inert
high performance ceramic materials
by deposition of bioactive braze
DFG/
FI 975/16-1
02/201201/2014
Entire project:
€ 380,000
Own share:
€ 190,000
Promoting of young researcher
Diploma Theses
Duffy, MP.
34
2011
IZKF Aachen Progress Report 2011
RWTH Aachen,
Faculty of Medicine
(Biomedical
Engineering),
Department of Dental
Materials and Biomaterials Research (ZWBF)
Physiological bone modeling and remodeling
simulation and the development of an
osteocyte computational communication
network
Project Funding
|
Medicine and Technology
| T9-2
2.1.
Staff: ½ TV-L 13 (Kant S.)
Materials/Travel expenses 2011: € 7,000
Investments/Equipment 2011: –
The function of the desmosomal cadherin desmoglein 2 for
cardiac force transmission and force generation
Leube R. E. (Institute of Molecular und Cellular Anatomy)
Hoffmann B. (Institute of Complex Systems)
The following milestones were accomplished:
– Optimization of conditions for isolation of cardiomyocytes from E18 mice
– Development of methods for purification of cardiomyocytes from trypsinized heart tissue
– Immunohistological characterization of cultured
cardiomyocytes
– Establishment of force measurements of single
murine cardiomyocytes
– Establishment of defined micro-colony formations on elastomeric substrates
– Assessment of histological and ultrastructural
alterations in desmoglein 2-mutant hearts
– Light microscopic identification of foci with
dying cardiomyocytes and calcification from 2
weeks onwards with subsequent collagen fibre
accumulation (see Figure 1)
– Immunohistologic detection of microlesions
with abundant CD45+ immune cells
– Electron microscopic detection of intercalated
disc dissociation, disturbed sarcomer structure,
altered Z-discs, increased autophagic vacuoles, and swollen mitochondria
– Quantification of desmosomal intercalated disc
expression
– Decrease of desmoglein 2, but no changes in
desmoplakin, plakoglobin, plakophilin, desmocollin 2, N-cadherin, and `-catenin as determined by semiquantitative immunohistology
and immunoblotting
– Acquisition of fetal hearts from wildtype and
desmoglein 2 mutant mice for the assessment
of very early stages of cardiac alterations
Figure 1: Histology of myocardial lesions in 2-6 week old desmoglein 2 mutants (mt/mt).
Azan stains are shown at low and high magnification in (a-c) and (a’-c’), respectively. Corresponding Kossa stains are presented in (a’’-c’’). Note that the lesions in 2-week-old desmoglein 2 mutant hearts are cell-rich (a’, a’’; stars) and contain
calcifications (a’’). In contrast, lesions of 6-week-old mutants show increasing amounts of collagen-rich extracellular matrix
(c, c’, arrowheads) and some calcified cardiomyocytes (c’’). In 4 week-old mutants, lesions with different amounts of collagen
deposition are found (b, b’): a lesion with low collagen content (star) is next to a lesion with high collagen content (arrowhead).
Scale bars, 1 mm in (a-c) and (a’’-c’’); 100 —m in (a’-c’). [The figure is taken from Kant et al., 2012, Cell Tissue Res, in press.]
IZKF Aachen Progress Report 2011
35
2.1.
Project Funding
|
| T9-2
Medicine and Technology
Publications
IZKF relevant, project associated
1. Krusche CA, Holthöfer B.; Hofe V., van de
Sandt AM, Eshkind L., Bockamp E., Merx MW,
Kant S., Windoffer R., Leube RE (2011) Desmoglein 2 mutant mice develop cardiac fibrosis and dilation. Basic Res Cardiol [IF 6.12]
2. Kant S, Krull P, Eisner S, Leube RE, Krusche
CA (2011) Histological and ultrastructural abnormalities in murine desmoglein 2-mutant
hearts. Cell Tissue Res in press [IF 2.8]
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Joint proposal of 5
independent groups for
a Helmholtz Virtual-Institute (spokesperson:
Prof. R. Merkel/FZJ
Combining nanotechnology
with functional imaging for
elucidating pathogenesis
and improving diagnostics of
the diseased heart
Helmholtz
Gemeinschaft
5 year
proposal
Application
submitted
(01/12)
New methods for a systems
level understanding of cell
mechanics
BMBF
3 year
grant
06/09-05/12
Grant-Nr.
0315501A
(Vice Spokesperson:
Prof. R. Leube/MOCA)
Joint grant of 4
independent groups
Spokesperson
Dr. Bernd Hoffmann
Promoting of young researcher
Doctoral Theses
36
Krull, P.
Ongoing
RWTH Aachen,
Medical Faculty
Kant, S.
Ongoing
RWTH Aachen,
Alterations in adhesion and signaling of mutant
Faculty of Mathematics, desmoglein 2 as inducers of cardiomyopathy
Computer Science and
Natural Sciences
IZKF Aachen Progress Report 2011
Correlation of osteopontin expression with
lesions and aseptic inflammation in the heart
of desmoglein 2 mutant mice
Project Funding
|
Medicine and Technology
| T9-3
2.1.
Staff: ½ TV-L 13 (Beckmann R.)
Materials/Travel expenses 2011: € 6,400
Investments/Equipment 2011: –
The potential of mechanically stimulated programmable cells
of monocytic origin in cartilage regeneration
Pufe T. (Department of Anatomy and Cell Biology)
Rath B. (Department of Orthopaedic Surgery)
Tingart M. (Department of Orthopaedic Surgery)
The aim of treating chondral defects after injury
or degenerative processes is to reconstruct the
cartilage structure. Especially with the aspect of
increased population longevity, development of
new therapeutic strategies is necessary to prevent
early onset of osteoarthritis in younger people.
Even though a couple of treatment options are
available, most of them do not meet the criteria
for optimal cartilage regeneration. The goal is to
restore hyaline cartilage on the joint surface. One
therapeutic strategy is cartilage tissues engineering. In this process, cartilage cells were seeded
and cultured in special 3-D cell carries/matrices.
The mechanical properties of the implanted matrix are of particular importance for short and
long-term therapy/success. But this procedure is
restricted. Because of the limitation of the number of isolated chondrocytes from a knee biopsy,
an expansion of these cells in monolayer without
mechanical stimulation leads to fast dedifferentiation into fibrochondrocytes. Therefore other cell
sources are necessary. Moreover, this two phase
treatment is, beside the high stress for the patient
during the second operation procedures, also associated with the risk of developing an additional
degenerative lesion (Donor-site morbidity). An alternative is the use of blood stem cells (Programmable Cells of Monocytic Origin – PCMOs) which
can be differentiated to the chondrogenic lineage
by extrinsic factors like growth factors and mechanical stimuli.
In 2011, the isolation of PCMOs from buffy coats
was established by the Department of Anatomy
and Cell Biology. The cells where mounted in a
collagen I hydrogel (Arthro Kinetics (Esslingen,
Germany)) and exposed to a daily mechanical
load for 4h over a period of 10 days. The cell/matrix constructs were incubated and stimulated in a
special designed bioreactor (Institute for General
Mechanics, PD Dr.-Ing. M. Stoffel).
The proposal of our planned animal experiment
for further evaluation of the PCMOs or chrondocytes seeded collagen gels in the göttinger minipig is under review by Dr. Scherer at this time.
Figure 1: PCMOs in the collagen I gel after mechanical stimulation. Arrow heads indicate the
PCMO cells in the gel. Cell shape is roundish
chondrocyte-like. Bar = 50 —m
IZKF Aachen Progress Report 2011
37
2.1.
Project Funding
|
| T9-3
Medicine and Technology
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Tingart, M.
Process development and testing
in order to improve cartilage tissue
replacement
11/200910/2011
€ 138,000
Stoffel, M.
Tingart, M.
Quality management of regenerative
BMBF-0315577F -09/2012
biomaterials for cartilage and meniscus
tissue replacement
€ 102,000
Pufe, T.
The role of VEGF in osteoarthritis
€ 325,000
DFG-Ti287/2-1
DFG
PU 214/3-2
-07/2012
Promoting of young researcher
Diploma Theses
Houben, A.
38
2011
IZKF Aachen Progress Report 2011
RWTH Aachen,
Biology
The expression of VEGF in chondrocytes due
to mechanical forces
Project Funding
|
Medicine and Technology
| T10
2.1.
Funding period: 01.07.2011 - 30.06.2014
Staff : –
Materials 2011: € 16,000
Investments/Equipment 2011: –
The Impact of Biomaterial Surface Topology on Differentiation
of Pluripotent Stem Cells into Cardiomyocytes
Zenke M. (Institute of Biomedical Engineering – Cell Biology)
in collaboration with A. Böker
(Institute for Macromolecular Materials and Surfaces, RWTH Aachen University, Aachen, Germany)
Recent progress in stem cell research allows
reprogramming and induction of pluripotency in
somatic cells by a defined set of transcription
factors, referred to as induced pluripotent stem
cells (iPS cells). iPS cells exhibit properties very
similar to embryonic stem cells (ES cells), e.g.
the potential to generate cells of all 3 germlayers
(ectoderm, endoderm and mesoderm), including cardiomyocytes. Thus, iPS cells offer unique
opportunities for the generation of disease- and
patient-specific cells for use in disease modelling,
drug development and cellular therapy.
In our previous work we screened our Biomaterial
Bank for materials that support and/or enhance
the differentiation of murine pluripotent stem cells
towards cardiomyocytes (in collaboration with
J. Groll and M. Möller, Institute for Textile and
Macromolecular Chemistry, RWTH Aachen University, Aachen, Germany). This projects aims
at extending these results to the human system.
To this end a large panel of human iPS cell lines
were generated with vectors containing the four
reprogramming transcription factors Oct4, Sox2,
c-Myc and Klf4 (in collaboration with C. Baum,
Hannover Medical School, Hannover, Germany;
O. Brüstle, Life & Brain, Bonn, Germany; H. R.
Schöler, Max-Planck-Institute for Molecular Biomedicine, Münster, Germany; Figure 1). iPS cells
were subjected to differentiation in embryoid
body (EB) assays and cells readily developed
into cardiomyocytes, including pacemaker cells.
Initial studies on testing iPS cell differentiation on
biomaterials are ongoing.
Figure 1: Human iPS cells were obtained with
the reprogramming factors Oct4, Sox2, c-Myc
and Klf4. Emerging iPS cells (arrow) on mouse
feeder layer express the ES cell marker Tra-1-60
(green; top panel). Established iPS cell line exhibits the characteristic morphology of ES cells
(lower panel). Scale bar, 1mm.
IZKF Aachen Progress Report 2011
39
2.1.
Project Funding
|
| T10
Medicine and Technology
Publications
IZKF relevant, project associated
1. Ding, X., Lin, Q., Ensenat-Waser, R., RoseJohn, S. and Zenke, M. (2011). Polycomb
group protein Bmi1 promotes hematopoietic
cell development from ES cells. Stem Cells
Dev. 21, 121-132. [IF 4.791]
2. Hoss, M., Apel, C., Dhanasingh, A., Suschek,
C. V., Hemmrich, K., Salber, J., Zenke, M. and
Neuss, S. (2011). Integrin alpha4 impacts on
differential adhesion of preadipocytes and
stem cells on synthetic polymers. J. Tissue
Eng. Reg. Med., in press. [IF 3.86]
3. Ko, K., Reinhardt, P., Tapia, N., Schneider, R.
K., Araúzo-Bravo, M. J., Han, D. W., Greber,
B., Kim, J., Kliesch, S., Zenke, M. and Schöler,
H. R. (2011). Evaluating the potential of putative pluripotent cells derived from human testis. Stem Cells 29, 1304-1309. [IF 7.871]
4. Müller, M., Stockmann, M., Malan, D., Wolheim, A., Tischendorf, M., Linta, L., Katz, S.F., Lin, Q., Latz, S., Brunner, C., Wobus, A.
M., Zenke, M., Wartenberg, M., Böckers, T.
M., von Wichert, G., Fleischmann, B., Liebau,
S. and Kleger, A. (2011). Ca2+-activated K+channels - New tools to induce cardiac commitment from pluripotent stem cells in mice
and men. Stem Cell Rev. and Rep., in press.
[IF 3.766]
5. Neuss, S., Denecke, B., Gan, L., Lin, Q., Bovi,
M., Apel, C., Wöltfe, M., Dhanasingh. A., Salber, J., Knüchel, R. and Zenke, M. (2011).
Transcriptome analysis of MSC and MSC-derived osteoblasts on Resomer LT706 and PCL:
Impact of biomaterial substrate on osteogenic
differentiation. PLoS ONE, e23195. [IF 4.411]
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Zenke, M.
Reprogramming and somatic memory
in ES cell/hematopoietic cell hybrids
DFG Ze 432/51/2
04/200806/2014
€ 518,800
Zenke, M.
Reprogramming of and programming
by mesenchymal stem cells (MSC)
DFG Ze 432/6-1
11/201010/2013
€ 195,000
Zenke, M.
Wagner, W.
StemCellFactory: Automatic production, EU/Bio.NRW
expansion and differentiation of induce
pluripotent stem cells (iPS cells)
11/201010/2013
Total
volume
€ 5,26 M
€ 441,000
Promoting of young researcher
Doctoral Theses
40
Hoß, M.
Ongoing
RWTH Aachen,
Faculty 1
Germline-derived pluripotent stem cells for
tissue engineering
Qin, J.
Ongoing
RWTH Aachen,
Faculty 1
Towards enhancing the differentiation potential
of human iPS cells
IZKF Aachen Progress Report 2011
2.1.
IZKF Aachen Progress Report 2011
41
PROJECT FUNDING
Cardiovascular Research
In 2011, the IZKF funded 10 projects with € 393,342 in the research focus
area Cardiovascular Research.
2.2.
Project Funding
|
Cardiovascular Research
PROJECT FUNDING
Cardiovascular Research
FINAL REPORTS
K1 | JOINT RESEARCH PROJECT Schober | 01.07.2008 - 30.06.2011
Endothelial progenitor cell-based therapies assisted by molecular and technical
measures
44
p. 46
K1-1 | Schober | 01.07.2008 - 30.06.2011
EPC subpopulations and endothelial function after stent implantation
and myocardial infarction
p. 47
K1-2 | Liehn | 01.07.2008 - 30.06.2011
Endothelial progenitor cells in myocardial infarction: recruitment mechanisms
p. 49
K1-3 | Vogt | 01.07.2008 - 30.12.2011
Construction and development of polymer-based stents with shape memory
effect and proendothelial coating
p. 51
K1-4 | Bernhagen | 01.07.2008 - 15.08.2011
Role of MIF in eEPC transplantation in murine and porcine models
of myocardial infarction
p. 52
K 1-5 | Günther | 01.07.2008 - 30.06.2011
The molecular effects of biofunctional pro-EPC mini-stents
p. 55
K2 | Schober | 01.07.2009 - 31.10.2011
CXCR7 and vascular wound healing by smooth muscle progenitor cells (SPCs)
p. 56
K3 | Suschek | 01.07.2009 - 30.11.2011
Modulation of local and systemic nitric oxide dependent metabolism by topical
dermal application of nitric oxide
p. 57
IZKF Aachen Progress Report 2011
Project Funding
|
Cardiovascular Research
2.2.
PROGRESS REPORTS
K4 | Schober | 01.07.2011 - 30.06.2014
MicroRNA-147 in atherogenesis
p. 59
K5 | Bernhagen | 01.07.2011 - 30.06.2014
Functional role of platelet-derived MIF in atherosclerosis
p. 60
K6 | Burgmaier/Krüger | 01.07.2011 - 30.06.2014
Proatherogenic effects of c-peptide in chronic kidney disease
p. 62
IZKF Aachen Progress Report 2011
45
2.2.
Project Funding
|
Cardiovascular Research
|
K1
Funding period: 01.07.2008 - 30.06.2011
Materials 2011: € 82,524
Investments/Equipment 2011: –
Endothelial progenitor cell-based therapies assisted by
molecular and technical measures
Schober A. (Institute for Molecular Cardiovascular Research)
The role of endothelial progenitor cells (EPCs) in
atherosclerosis and its sequelae such as myocardial infarction and restenosis is of great importance for clinical treatment strategies. However,
the effects of EPCs in atherosclerosis are unclear
because the evidence from animal and clinical
studies is contradictory. Moreover, the identity
and functional role of the rather heterogeneous
subpopulations of adult EPCs in comparison to
embryonic EPCs remains to be determined. This
joint project aims to investigate novel aspects of
determination and isolation of EPCs from humans,
mice and pigs in an interdisciplinary approach.
1. Characterization of CD14 positive, monocytic
and CD34+ EPC subpopulations, which share
some phenotypic features, in arterial repair, endothelial regeneration and dysfunction as well
as in restenosis following stent implantation in
patients with coronary artery disease.
2. Identification of molecular pathways that regulate EPC function in myocardial infarction and
vascular injury in transgenic mouse models.
3. Development of segmented polyurethane stents
to enable imaging in a pig model of restenosis.
4. MIF-mediated mechanisms of adult and embryonic EPCs to improve myocardial function following infarction.
5. Development and in vivo characterization of biofunctionalized nitinol stents to improve EPC-dependent endothelialization in a mouse model.
Publications
IZKF relevant, project associated
1. Söhnlein O., Wantha S., Simsekyilmaz S.,
Döring Y., Megens R.,T., Mause S.F., Drechsler
M., Smeets R, Weinandy S., Schreiber F., et
al. (2011). Neutrophil-derived cathelicidin protects from neointimal hyperplasia. Sci Transl
Med 3, 103ra198 [IF3.292]
Promoting of young researcher
Doctoral Theses
Li, X.
Ongoing
RWTH Aachen,
Faculty 1
The molecular effects of biofunctional pro-EPC
mini stents
NazariJahantigh, M.
Ongoing
RWTH Aachen,
Faculty 1
EPC subpopulations and endothelial function
after stent implantation
Subramanian,
P.
Ongoing
RWTH Aachen,
Faculty 1
EPC subpopulations and endothelial function
after myocardial infarction
Postdoctoral lecture qualification
Hristov, M.
46
2011
IZKF Aachen Progress Report 2011
RWTH Aachen,
Medical Faculty
The role of circulating angiogenic cells in
endothelial regeneration and vascular risk
prediction
Project Funding
|
Cardiovascular Research
|
K1-1
2.2.
Funding period: 01.07.2008 - 30.06.2011
Staff: TV-L 9 (Heyll K.)
Materials 2011: € 15,750
Investments/Equipment 2011: –
EPC subpopulations and endothelial function after stent
implantation and myocardial infarction
Schober A. (Institute for Molecular Cardiovascular Research)
We suggest that the number of peripheral CD14lowCD16+ monocytes in contrast to CD14high
monocytes and classical EPCs specifically correlate with the endothelial function in patients
with coronary heart disease and can predict future cardiovascular events. In addition, we found
that CD14lowCD16+ monocytes were mobilized
into the circulation after an initial expansion of
CD14high monocytes in patients with acute myocardial infarction. We studied patients after acute
myocardial infarction and patients with stable
coronary heart disease. Moreover, the presence
of cardiovascular risk factors and the plasma
levels of NO, SDF-1alpha and angiopoetin were
correlated with the different EPC subpopulations.
Percutaneous stent implantation plays an important role in the treatment of obstructive coronary
atherosclerosis. The re-narrowing of dilated coronary arteries, called restenosis, however, limits
the long term success of stent implantation in
30-40% of patients, necessitating repeated interventions. Reendothelialization is critical for the
long term success of this therapeutic approach.
We therefore tested the hypothesis that EPCs
and CD14lowCD16+ monocytes inversely correlate with the risk for in-stent restenosis. We
study the number of peripheral CD14lowCD16+
monocytes in contrast to CD14high monocytes
and classical CD34+VEGFR2+ EPCs and cor-
relate the number of each subpopulation with the
endothelial function as determined by flow-mediated dilatation of arteries and the intima-medial
thickness of the carotid artery with ultrasonography in patients with coronary heart disease.
Alternatively, the studied cell populations will be
correlated with presence of cardiovascular risk
factors. In addition, we analyze the fraction of peripheral CD14lowCD16+ and CD14high monocytes
in the circulation of patients with acute myocardial infarction. Moreover, theplasma levels of NO,
SDF-1alpha and angiopoetin will be correlated
with the different EPC subpopulations. We also
evaluate whether CD34+VEGFR2+ EPCs and
CD14lowCD16+ monocytes in the peripheral blood
of patients after stent placement inversely correlate with the risk for in-stent restenosis. We performed flow cytometry measurements in patients
with stable coronary heart disease and patients
after acute myocardial infarction. The EPCs, the
CD14lowCD16+ monocytes and the CD14high
monocytes were quantified. To evaluate the significance of peripheral CD14lowCD16+ monocytes,
CD14high monocytes and CD34+VEGFR2+
EPCs in patients after coronary stent implantation, we studied patients after elective coronary
stent implantation. The EPC subpopulations were
quantified before, one day after stent implantation
and 6 months after stent implantation.
Publications
IZKF relevant, project associated
1. Hristov M, Weber C. (2011) Differential role of monocyte subsets in atherosclerosis. Thromb Haemost
106:757-62 [IF 4.7]
IZKF Aachen Progress Report 2011
47
2.2.
Project Funding
|
Cardiovascular Research
|
K1-1
Promoting of young researcher
Doctoral Theses
NazariJahantigh, M.
Ongoing
RWTH Aachen,
Faculty 1
EPC subpopulations and endothelial function
after stent implantation
Subramanian,
P.
Ongoing
RWTH Aachen,
Faculty 1
EPC subpopulations and endothelial function
after myocardial infarction
Postdoctoral lecture qualification
Hristov, M.
48
2011
IZKF Aachen Progress Report 2011
RWTH Aachen,
Medical Faculty
The role of circulating angiogenic cells in
endothelial regeneration and vascular risk
prediction
Project Funding
|
Cardiovascular Research
|
K1-2
2.2.
Funding period: 01.07.2008 - 30.06.2011
Staff: SHK (Konschalla S., Kroch A.)
Materials 2011: € 25,374
Investments/Equipment 2011: –
Endothelial Progenitor Cells in Myocardial Infarction:
Recruitment Mechanisms
Liehn E. (Institute for Molecular Cardiovascular Research)
Despite considerable progress, cardiovascular
diseases (CVD) represent the number one cause
of death world-wide. Stem cell or progenitor cell
therapy, using embryonic stem cells or endothelial progenitor cells (EPCs) has proven to have a
substantial potential to regenerate injured cardiac
and vascular tissues. Nevertheless, the underlying mechanisms are not clearly understood and
are subject of intensive investigation.
First, we can demonstrate the crucial role of
Cxcr4 in endogenous remodeling processes after
MI, contributing to inflammatory/progenitor cell
recruitment and neo-vascularization, whereas its
deficiency limits infarct size and causes adaptation to hypoxic stress. Moreover, we were able to
show that angiogenesis is a multi-step process,
involving a complex interplay between the endothelium, pro-angiogenic factors and recruited
EPCs. Here, we have identified a pivotal role for
EPC-derived pro-angiogenic MIF, VEGF and MIF
receptors in EPC recruitment following hypoxic
challenge, EPC differentiation and subsequent
tube and vessel formation, whereas CXCL12, a
mediator of early EPC recruitment, does not contribute to the remodeling process. These findings
have important implications for the devising of
pro-angiogenic therapies in the treatment of CVD
and point out the need to precisely identify the
molecular players and sequence of steps in new
vessel formation.
Further, to study the recruitment mechanisms of
EPCs after myocardial infarction, we used lentiviral infected EPCs to overexpress SDF-1. Intramyocardial application of lentiviral infected EPCs
is associated with a significant improvement of
myocardial function after infarction, in contrast to
an intracoronary application. Histological results
revealed a significant augmentation of neovascularization, lower collagen content, higher numbers
of inflammatory cells and remarkable alterations
of apoptotic/proliferative processes in infarcted
areas after cell transplantation.
Various studies have made an effort to elucidate
and scrutinize the mechanisms, which were responsible for beneficial effects in infarcted myocardium following cell-based therapy. Repairing
vascular integrity, stimulating neovascularisation,
attenuated loss of myocardial function, modulation of inflammatory processes or paracrine effects might be in part responsible for cardiac protection. In the same way, genetically altered cells
or cells preconditioned with growth factors have
shown an additional impact on improvement of
myocardial function.
The results of different studies lead to the conclusion that attenuation of myocardial dysfunction
after cell transplantation seems to be a combination of different mechanisms. Different cell types
were suggested to exert different mechanisms
in improving myocardial function. Whereas the
main mechanism of transplanted endothelial
cells or EPCs may be improved neovascularization, through a better nutrition of infarcted regions
and a partially reconstituted vascular network,
the main beneficial effect of transplanted myocardial cells seems to be an additional reservoir
of contractile cells. However, paracrine effects
of both cell types have also been suggested as
important mechanisms. Based on these findings,
our hypothesis was that the endothelial progenitor cells (EPCs) transplantation should improve
neovascularization and reconstitute vascular
structures in damaged myocardial areas. This
improved “preconditioning” should increase the
survival chances and the benefit of transplanted
foetal myocardial cells in damaged myocardium.
Indeed, our results has demonstrated that sequential transplantation of different cell types
further improves cardiac function concurrent with
reverse LV remodeling compared with a single
cardiomyocytes transplantation.
In conclusion, although we elucidated same
mechanisms of improving ventricular remodelling
by transplantation of EPCs and fine-tuning che-
IZKF Aachen Progress Report 2011
49
2.2.
Project Funding
|
Cardiovascular Research
|
K1-2
mokines by active peptide agonists or antagonists, many other studies are necessary to develop efficient therapeutical strategy for improving
function of the heart, and patient’s prognosis after
myocardial infarction.
Publications
IZKF relevant, project associated
1. Liehn EA, Piccinini AM, Koenen RR, Soehnlein O, Adage T, Fatu R, Curaj A, Popescu A,
Zernecke A, Kungl AJ, Weber C (2010). A new
MCP-1/CCL2 competitor limiting neointima
formation and myocardial ischemia-reperfusion injury in mice. J Am Coll Cardiol 56:184757. [IF 11.460]
2. Liehn EA, Tuchscheerer N, Kanzler I, Drechsler
M, Fraehmos L, Schuh A, Koenen R, Zander
S, Soenhlein O, Hristov M, Grigorescu G, Urs
AO, Leabu M, Bucur I, Merx MW, Zernecke A,
Ehling J, Gremse F, Lammers T, Kiessling F,
Bernhagen J, Schober A, Weber C. Doubleedged role of the CXCL12-CXCR4 axis in
experimental myocardial infarction. J Am Coll
Cardiol 2011; 58:2415-23. [IF 14.210]
3. Schuh A, Sasse A, Konschalla S, Kroh A,
Merx MW, Weber C, Liehn EA. Repetitive
transplantation of different cell types sequentially improves heart function after infarction.
J Cell Mol Med. 2011; Epub ahead of print. [IF
4,603]
4. Schuh A, Kroh A, Konschalla S, Liehn EA, Sobota R, Biessen E, Bot I, Sasse A, Weber C.
Myocardial regeneration by transplantation of
modified endothelial progenitor cells expressing SDF-1 in a rat model. J Cel Moll Med 2011,
in press. [IF 4,603]
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Bernhagen, J.
Liehn, E.
Structural and functional characterization of MIF/ Chemokine receptors
axis in atherisclerosis and myocardial
infarction
DFG
01/201112/2013
Promoting of young researcher
Doctoral Theses
Kroh, A.
Ongoing
RWTH Aachen,
Faculty 1
Myocardial regeneration after transplantation of
modified endothelial progenitor cells in a rat model
of myocardial infarction
Konschalla, S.
Ongoing
RWTH Aachen,
Faculty 1
The role of SDF-1 after endothelial progenitor cells
transplantation in a mouse model of myocardial
infarction
Awards
Hans und Gertie Fischer Stiftungspreis 11/2011
50
IZKF Aachen Progress Report 2011
Project Funding
|
Cardiovascular Research
|
K1-3
2.2.
Funding period: 01.07.2008 - 30.06.2011
Staff: ½ TV-L 13 (Borinski M.)
Materials 2011: € 17,100
Investments/Equipment 2011: –
Construction and development of polymer-based stents with
shape memory effect and proendothelial coating
Vogt F. (Department of Medicine I)
Biodegradable polyesteramide (BAK, Bayer,
Leverkusen) and shape-memory polymer carbothane® (SMP, Lubrizol, Belgien) were melted into
monofilaments. Biocompatibility tests demonstrated SMP-mediated facilitation of attachment
endothelial progenitor cells (EPCs); also, vitality
of EPCs was improved. Furthermore, SMP stimulated migration of EPCs, human umbilical vein
endothelial cells (HUVECs) and smooth muscle
progenitor cells (SMPCs). In contrast, polyesteramide inhibited migration of SMPCs, HUVECs
and EPCs.
Polymeric monofilaments were further processed
to stents in a braiding machine, and process parameters such as braiding ankle, stent diameter,
stent length and number of monofilaments were
varied and adapted to specific requirements.
Biodegradable polyesteramide monofilaments
revealed insufficient strength to be processed by
braiding. First SMP prototypes were evaluated at
37°C and displayed form instability by reducing
monofilament length and thereby reducing stent
diameter. Therefore, a heat fixation of SMP on
an mandrel at 125°C for 10-20 min. was applied,
which resulted in the melting of crossing points
and an increased radial stiffness. Mechanical
tests of stents revealed appropriate dilatation
behaviour and minimal recoil after balloon dilatation. To evaluate in-vivo biocompatibility and
performance of prototypic braided stents, in an
adapted rat in-stent restenosis model, we demonstrated feasibility of implantation of braided
stent prototypes as a dual layer scaffolded by a
bare-metal stent.
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Borinski, M.
Vogt, F.
Characterization of expression and
role of angio-associated migratory cell
protein in specific mononuclear cell
subpopulations and atherosclerotic
lesions of patients with diabetes
mellitus and chronic kidney disease
Deutsche
Herzstiftung e.V.
applied
Promoting of young researcher
Doctoral Theses
Borinski, M.
Ongoing
RWTH Aachen,
Medicine
Development and characterization of polymerbased proendothelial stents
IZKF Aachen Progress Report 2011
51
2.2.
Project Funding
|
Cardiovascular Research
|
K1-4
Role of MIF in eEPC transplantation in murine and porcine
models of myocardial infarction
Bernhagen J. (Institute of Biochemistry and Molecular Cell Biology)
Koch K.C. (Department of Internal Medicine I)
Schäfer W. (Department of Nuclear Medicine)
Angiogenic endothelial progenitor cells (EPCs)
are mobilized during myocardial infarction (MI)
and have a promising therapeutic potential. EPCs
also have been assumed to play a critical role in
wound regeneration. „Embryonal“ EPCs (eEPCs)
show a favorable behavior and may be expanded
in vitro for syngenic/xenogenic transplantation
purposes. eEPCs carry not only angiogenic
VEGF but also additional angiogenic factors such
as the chemokine-like cytokine MIF. As MIF exerts protective effects in MI and during wound
regeneration, the project has focused on the
links between MIF and EPCs during these pathophysiological situations. One main focus was on
the underlying mechanisms of EPC recruitment
and the comparison of the angiogenic potential
of MIF upon hypoxic/ischemic challenge. Mouse
EPCs and murine eEPCs were analyzed for the
secretion of angiogenic factors/chemokines and
components of the MIF/CXC chemokine receptor
axis. Hypoxic stimulation induced an up-regulation of the expression of CXCR2 and CXCR4 but
not CD74 on EPCs and triggered the secretion of
CXCL12, CXCL1, MIF, and VEGF. These EPCderived factors stimulated the chemotactic and
transmigration activity capacity of EPCs, with MIF
and VEGF exhibiting the most potent effects under hypoxic conditions. MIF-, VEGF-, CXCL12-,
and CXCL1-stimulated EPCs enhanced tube
formation in vitro, with again MIF and VEGF
exhibiting the strongest effect following hypoxia. Tube formation in an in
vivo implantation model utilizing angiogenic factor-loaded matrigel plugs
was only promoted by VEGF. Co-loading with eEPCs led to enhanced tube
formation by CXCL12 but not the other
factors, whereas MIF was the only factor that induced differentiation towards
an endothelial and SMC phenotype.
Surprisingly, CXCL12, a main chemoattractant for smooth muscle progenitors, inhibited SMC differentiation.
In conclusion, we have identified a pivotal role for EPC-derived MIF, VEGF
and MIF receptors in EPC recruitment
Figure 1: Schematic summarizing the proposed role of EPCs and the studied following hypoxic challenge, EPC difangiogenic factors/chemokines in neo-angiogenesis. After destruction of tissue, an ferentiation and subsequent tube and
inflammatory reaction is induced by the release of cytokines/angiogenic chemo- vessel formation, whereas CXCL12,
kines. These activate circulating EPCs, which upregulate their angiogenic chemo- a mediator of early EPC recruitment,
kine receptors due to the hypoxic challenge, adhere and transmigrate to the site does not contribute to the remodeling
of injury. Here, together with monocytes they integrate into tube structures, and
differentiate into mature endothelial cells (“vessel formation”). The data suggest that process (Figure 1).
MIF and VEGF are critical players in the earlier processes. Also MIF, but surprisingly not CXCL12, are important in the later stages including fully functional vessel
formation.
52
IZKF Aachen Progress Report 2011
Project Funding
|
Cardiovascular Research
|
K1-4
2.2.
IZKF Aachen Progress Report 2011
53
Funding period: 01.07.2008-30.06.2011
Staff: 1 TV-L 9 (Decker L., Hoch B.)
Materials 2011: € 8,500
Investments/Equipment 2011: –
Publications
IZKF relevant, project associated
1. Simons D, Grieb G, Hristov M, Pallua N, Weber
C, Bernhagen J, Steffens G (2011) Hypoxiainduced endothelial secretion of macrophage
migration inhibitory factor and role in endothelial progenitor cell recruitment. J Cell Mol Med
15:668-678 [IF 5,228]
2. Kanzler I, Liehn EA, Koenen RR, Weber
C (2011) Anti-inflammatory therapeutic approaches to reduce acute atherosclerotic complications. Curr Pharm Biotechnol 13:37-45 [IF
3.455]
3. Liehn EA, Tuchscheerer N, Kanzler I, Drechsler
M, Fraemohs L, Schuh A, Koenen RR, Zander
S, Soehnlein O, Hristov M, Grigorescu G, Urs
AO, Leabu M, Bucur I, Merx MW, Zernecke
A, Ehling J, Gremse F, Lammers T, Kiessling
F, Bernhagen J, Schober A, Weber C (2011)
Double-edged role of the CXCL12/CXCR4
axis in experimental myocardial infarction. J
Am Coll Cardiol 58:2415-2423 [IF 14.292]
4. Grieb G, Piatkowski A, Simons D, Hörmann N,
Dewor M, Steffens G, Bernhagen J, Pallua N
(2011) Macrophage migration inhibitory factor
is a potential inducer of endothelial progenitor
cell mobilization after flap operation. Surgery
151:268-277 [IF 3,603]
5. Grieb G, Simons D, Steinberger H, Vollmar A,
Bernhagen J, Pallua N. (2011) Improved in vitro cultivation of endothelial progenitor cells as
basis for dermal substitutes with enhanced angiogenic capabilities Langenbecks Arch Surg
396:1255-1262 [IF 1,951]
6. Lüdike P, Hendgen-Cotta U B, Sobierajski J,
Totzeck M, Reeh M, Dewor M, Lue H, Krisp
C, Wolters D, Kelm M, Bernhagen J*, Rassaf T* (2012) Cardioprotection through Snitros(yl)ation of macrophage migration inhibitory factor. Circulation, in press [IF 14.816]
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Bernhagen, J.
MIF and CXCR2 in liver fibrosis
within SFB-TRR “Organ fibrosis”
DFG
SFB-TRR57
Project P07
01/200912/2012
€ 350,000
Bernhagen, J.
(Liehn, E.)
Structural and functional characterization of MIF/ Chemokine
receptors axis in atherisclerosis
and myocardial infarction
DFG
BE 1977/4-2
TP1/DFGFOR809
07/201006/2013
€ 344,400
Rassaf, T.
Bernhagen, J.
Interaction between MIF and nitrite DFG
in myocardial infarction
Ra969/5-1
07/200906/2012
€ 43,000*
Bernhagen, J.
Regulation of NFgB/RelA activa- DFG
tion by MIF/CD74 and crosstalk
SFB-TRR116
with the CXC chemokine receptor Project A5
axis within SFB-TRR116 “Signal
integration, crosstalk mechanisms
and networks in inflammatory
cytokine function”
Applied
for:
07/201206/2016
Applied for:
€ 310,000
SFB & project
positively reviewed
on 1.2.2012; DFG
“Bewilligungsausschusssitzung” in
May 2012
Kraemer, S.
Bernhagen, J.
Novel anti-chemokine therapeutics BMBF
for inflammatory diseases and
Go-BIO
cancer
program Az
010131P7493
Applied
for:
01/201312/2015
Applied for:
€ 1,845,000
Review decisions
in March 2012 (1st
round) and July
2012 (final round)
2.2.
Project Funding
|
Cardiovascular Research
Bernhagen, J.
Hackeng, T.
(CARIM,
Maastricht)
et al.
|
K1-4
Intervention and imaging in
arterial remodelling: underlying
mechanisms and translational
strategies
DFG
IRTG1508/2
renewal application for 2nd
funding period
Applied
for:
04/201309/2017
Applied for:
€ 2,500,000**
On-site review in
July 2012
* Part Bernhagen only
** Bernhagen, J. is Spokesman of IRTG1508 and project head in 1 project (PhD5: ca. € 30.000,-)
and co-project head in 2 projects (PhD7, PhD8: ca. 2x € 15.000,- = 30.000,-)
Promoting of young researcher
Diploma Theses
Klasen, C.
2011
RWTH Aachen,
Faculty 1
Role of MIF and its receptors in B lymphocytes
Platen, C.
2011
FH Aachen/Jülich Secretion of the cytokine macrophage
migration inhibitory factor (MIF) following
inflammatory stimulation
Hennes, T.
2011
RWTH Aachen,
Faculty 1
Structure-activity-relationships of the MIF/CXCR
axis through application of so-called MIF-ELR
and MIF N-loop mutants
Kanzler, I.
Ongoing
RWTH Aachen,
Faculty 1
Therapeutic potential of MIF in angiogenesis:
novel insights and comparison with established
angiogenic factors
Gaffga, H.
Ongoing
RWTH Aachen,
Medical Faculty
Imaging and mechanisms of leukocyte recruitment
induced by MIF
Doctoral Theses
Postdoctoral lecture qualification
El Bounkari, O.
Ongoing
RWTH Aachen
Simons, D.
Ongoing
RWTH Aachen, CXCR4-based recruitment and metastasis
DKFZ Heidelberg processes (tentative title)
Awards
Physiology and pathophysiology of MIF receptor
complexes (tentative title)
Simons, D.; Grünenthal award of the Medical Faculty of RWTH Aachen University for the best clinicaltheoretical dissertation 2011
54
IZKF Aachen Progress Report 2011
Project Funding
|
Cardiovascular Research
|
K1-5
2.2.
Funding period: 01.07.2008 - 30.06.2011
Staff: TV-L 9 (Tupiec J, Pentschel A)
Materials 2011: € 15,800
Investments/Equipment 2011: –
The molecular effects of biofunctional pro-EPC mini-stents
Simsekyilmaz S., Günther E. (The Institute for Molecular Cardiovascular Research)
Klee D., Möller M. (Institute of Technical and Macromolecular Chemistry)
Grieß T., Schreiber F. (Institute of Textile Technology)
The first aim of the study was the development
of a coating system for immobilization of bioactive compounds for supporting the adhesion and
growth of endothelial cells and endothelial progenitor cells (EPCs). In addition to star-shaped
layerings of polyehtyleneglycole (star-PEG) that
minimize unspecific binding, coatings with ArgGly-Asp (RGD)-peptide, RGD sequence enabling
cell attachment, and the chemokine Gro-_ were
employed. Endothelial cell growth experiments
under static conditions demonstrated that starPEG surfaces functionalized with cRGD provide
adequate recognition motives for endothelial
cells, while a mixture of cRGD and Gro-_ was
required to enable EPC attachment. A significant
increased binding of smooth muscle cells (SMCs)
and mononuclear cells (MM6) was not observed
in any case of coating, whereas a reduced adhesion of smooth muscle progenitor cells (SPCs)
was seen by functionalizing with cRGD and Gro_. In vitro proliferation assays showed that cRGD
and Gro-_ together were only able to increase
proliferation of EPCs and had no effect on SMCs
and MM6 cells. These observations were not due
to cytotoxic effects. In vivo, the functionalizing
of nitinol-stents with cRGD and Gro-_ reduced
neointima formation in ApoE-/--mice 1 week after
implantation. Coating only with cRGD was not
sufficient to decrease neointimal hyperplasia.
We also concentrated on peptides for coatings to
adress neutrophils. Here, we identified cathelicidins (LL-37) as important mediators of neutrophildependent repair after arterial injury. The activity
of these effectors was based on their EPC-activating capacities: They enhanced EPC recruitment
and released regenerative growth factors. Both
mechanisms cooperated to promote re-endothelialization and to reduce the extent of neointima
formation. We translated this knowledge by designing a P-selectin, cRGD- and LL-37–coated
stent, which was effective in limiting in-stent stenosis and improved re-endothelialization.
Publications
IZKF relevant, project associated
1. Soehnlein O, Wantha S, Simsekyilmaz S,
Döring Y, Megens RT, Mause SF, Drechsler M,
Smeets R, Weinandy S, Schreiber F, Gries T,
Jockenhoevel S, Möller M, Vijayan S, van Zandvoort MA, Agerberth B, Pham CT, Gallo RL,
Hackeng TM, Liehn EA, Zernecke A, Klee D,
Weber C. (2011), „Neutrophil-Derived Cathelicidin Protects from Neointimal Hyperplasia“,
Sci Transl Med 3, 103ra98, [IF3.292]
Promoting of young researcher
Doctoral Theses
Simsekyilmaz, S. Ongoing
RWTH Aachen,
Faculty 1
Evaluation of biofunctionalized, covered mini-stents
in mouse-model
IZKF Aachen Progress Report 2011
55
2.2.
Project Funding
|
Cardiovascular Research
|
K2
Funding period: 01.07.2008 - 31.10.2011
Staff: TV-L 9 (Thiemann A.)
Materials 2011: € 15,250
Investments/Equipment 2011: –
CXCR7 and vascular wound healing by smooth muscle
progenitor cells (SPCs)
Schober A. (Institute for Molecular Cardiovascular Research)
The chemokine receptor CXCR7 plays a role in cell
survival, adhesion, tumor growth and development
by binding to CXCL12 (SDF-1_) and CXCL11 (ITAC). CCX771 is a highly specific CXCR7 ligand,
which has been shown to affect SDF-1_/ITAC binding to CXCR7 and modulate `-arrestin coupling.
We studied the role of CCX771 in atherosclerotic
vascular disease, such as neointima formation after
vascular injury and diet-induced atherosclerosis.
Wire-induced injury of the carotid artery was performed in Apoe-/- mice on a Western-type diet.
Mostly endothelial CXCR7 immunostaining was
evident at 1 week after injury. Mice were treated
with CCX771 (10mg/kg/d, s.c., n=8) or the solvent
Captisol (10%, n=8) for 28 days. Plasma CCX771
levels were sufficiently high to provide full receptor
coverage at trough. CCX771 reduced neointima formation by 35% due to a diminished neointimal macrophage content. SMC and T-cell content, however,
were not affected by CCX771. CXCL12-mediated
mobilization of Sca-1+/Lin- progenitor cells 24h after
injury was similar in CCX771- and Captisol-treated
mice.
In the atherosclerosis model, Apoe-/- mice on a
high-fat diet were treated with CCX771 (10mg/kg/d,
s.c., n=10) or Captisol (10%, n=10) for 3 months.
Analysis of the en face prepared thoracoabdominal aorta after Oil-Red-O staining demonstrated a
41% decrease of aortic lipid deposition in CCX771treated mice (P<0.05). Furthermore, the plaque
area in the aortic root was reduced by 39%
through CCX771 (P<0.05). Determination of
body weight, serum AST, ALT, creatinine, and
C-reactive protein revealed no differences between CCX771- and Captisol-treated mice in
the wire-injury and atherosclerosis model.
We demonstrate a protective role of the
CXCR7 ligand CCX771 in atherosclerotic
vascular disease.
Figure 1: Neointimal area after carotid wire
injury in ApoE-/- mice was reduced significantly by daily injection of the CXCR7 ligand
CCX771 for 28 days. In the control group
mice were treated with the vehicle Captisol.
Pentachrome stained carotid sections demonstrate diminished neointimal area (upper
panel). Quantification of the neointimal and
medial areas revealed that the neointimal
area was selectively reduced (lower panel).
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Weber, C.
Schober, A.
56
Role of the CXCL12 receptors CXCR4
and CXCR7 in atherosclerosis and
homeostasis of vascular cells
IZKF Aachen Progress Report 2011
DFG
(FOR809, TP4)
01/201102/2014
€ 532,200
Project Funding
|
Cardiovascular Research
|
K3
2.2.
IZKF Aachen Progress Report 2011
57
Funding period: 01.07.2008 - 30.11.2011
Staff: TV-L 13 (Opländer Ch.)
½ TV-L 13 (Volkmar Ch. M.)
Materials 2011: € 1,650
Modulation of local and systemic nitric oxide dependent
metabolism by topical dermal application of nitric oxide
Suschek C.V. (Department of Plastic Surgery, Hand Surgery)
The aim of this project is to evaluate a possible
local and systemic elevation of nitric oxide derivates and subconsequent physiological effects
by topically dermal application of nitric oxide
(NO). First, a nitrite based NO-donor cream was
developed and evaluated, which has significant
advantages over creams described in literature.
Furthermore, a device for generating gaseous
NO and 15N-NO was established. A deep penetration of NO through epidermis into skin could be
demonstrated by EPR-spectroscopy and FranzDiffusion-Cell experiments, which was accompanied by S-nitrosilation of skin proteins. Moreover,
5 min of topical NO-application significantly increased the local dermal blood flow and muscle
blood flow for 30 min in human volunteers. Further experiments could prove a translation of NO
and NO-derivates into the circulation system,
correlated with a significant drop of blood pressure without any signs of methaemoglobina. Additionally, the local increase of NO-derivates has
antithrombotic effects, thus, dermal NO-application prolonged local bleeding time (Ivy-Method)
and reduced induced platelet aggregation (BornMethod). In a case study of a patient with a critical perfusion reduced flap, the off-label use of
dermal NO-application could prevent revision
surgery by improving circulation in the flap. Thus,
dermal NO-application represents a therapeutic
tool against local impaired micro circulatory, e.g.
after skin transplantation or diabetic foot syndrome, and may also have beneficial systemic
effects, in particular, reduction of blood pressure.
Publications
IZKF relevant, project associated
1. Oplander C, Suschek, CV Dermal Nitrite Application: An Update. Journal of Investigative Dermatology: 131: 1763–1765 (2011) [IF
6.270]
2. Opländer C, Hidding H, Werners FB, Born M,
Pallua N, Suschek CV. Effects of blue light irradiation on human dermal fibroblasts. J Photochem Photobiol B 103(2): 118-25. (2011) [IF
2.116]
3. Oplander C, Romer A., Paunel-Görgülü A,
Fritsch T, van Faassen EE, Mürtz M, Bozkurt
A, Grieb G, Fuchs P, Pallua N, Suschek CV.
Kinetics and biological responses of dermal
application of nitric oxide in vivo: Therapeutical
potential in humans. Clinical Pharmacology &
Therapeutics (accepted Dez 2011) [IF 6.378]
4. Oplander C, Volkmar CM, Paunel-Görgülü A,
Fritsch T, van Faassen EE, Mürtz M, Grieb G,
Bozkurt A, Hemmrich K, Windolf J, Suschek
CV. Dermal application of nitric oxide significantly reduces blood pressure in humans. Nitric Oxide – Biol. Ch. (accepted Jan 2012) [IF
3.384]
2.2.
Project Funding
|
Cardiovascular Research
|
K3
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Opländer, C.
Impact of topical nitric oxide
application on human skin, skin cells
and intracellular nitric oxide derivates
DFG
OP 207/4-1
01.201212.2013
€ 198,065
rejected
Opländer, C.
Plasma Cell Interactions in
Dermatology (PlaCID)
DFG
04.201203.2015
€ 308,200
Promoting of young researcher
Doctoral Theses
Römer, A.
Ongoing
RWTH Aachen,
Medicine
Cutaneous application of acidified or pH-neutral
nitrite: Nitric oxide but not nitrite rapidly penetrates
human epidermis and alters local and systemic
status of nitrogen oxide species in vivo
VukadinovićWalter, B.
Ongoing
RWTH Aachen,
Medicine
UVA-induced phenoxyl radical formation:
A new cytotoxic principle in photodynamic therapy
Rösner, J.
Ongoing
RWTH Aachen,
Medicine
Redox-depend metal induced nitric oxid formation
Gombert, A.
Ongoing
RWTH Aachen,
Medicine
Method for the measurement of antioxdative
capacity in human blood plasma via nitric oxide
formation
Müller, T.
Ongoing
RWTH Aachen,
Medicine
Evaluation of nitric oxide release from aqueous
solution for medical proposes
Roser, S.
Ongoing
RWTH Aachen,
Medicine
Safety of dermal application of nitric oxide
Postdoctoral lecture qualification
Opländer, C.
58
IZKF Aachen Progress Report 2011
Ongoing
RWTH Aachen,
Medicine
Nonenzymatic nitric oxide generation in physiology
and therapy
Project Funding
|
Cardiovascular Research
|
K4
2.2.
IZKF Aachen Progress Report 2011
59
Funding period: 01.07.2011 - 30.06.2014
Staff: TV-L 9 (Heyll K.)
Materials/Travel expenses 2011: € 13,000
Investments/Equipment 2011: –
MicroRNA-147 in atherogenesis
Schober A. (The Institute for Molecular Cardiovascular Research)
We found that the expression of miR-147 continuously increases during atherosclerotic lesion formation in Apoe-/- mice using microRNA expression
profiling. MiR-147 has been shown to inhibit the
inflammatory response in macrophages. Therefore, we study the hypothesis that miR-147 has
a protective role in atherogenesis by promoting
an anti-inflammatory response in macrophages.
We have generated a transgenic mouse that harbours a conditional miR-147 allel and we will start
to breed these mice with mice that express crerecombinase in macrophages and vascular cells.
Using these mice, we will study the functional role
of miR-147 in atherosclerosis induced by feeding a high fat diet. Moreover, we found that the
expression of miR-147 in smooth muscle cells is
crucial in neointima formation following vascular
injury, because tamoxifen-induced deletion of the
miR-processing enzyme dicer in SMCs increases
neointima formation and significantly diminishes
the expression of miR-147 as demonstrated by
qRT-PCR array and in situ hybridisation. These
findings indicate a protective role of miR-147 in
vascular diseases.
2.2.
Project Funding
|
Cardiovascular Research
|
K5
Functional role of platelet-derived MIF in atherosclerosis
Bernhagen J. (Institute of Biochemistry and Molecular Cell Biology)
Macrophage migration inhibitory factor (MIF) is an
inflammatory cytokine und chemokine-like function
(CLF) chemokine, which promotes atherogenic
Figure 1: Stimulation of MIF secretion from purified human platelets
by thrombin.
leukocyte recruitment and lesion formation via the
chemokine receptors CXCR2 und CXCR4. It was
thought that ‘atherogenic’ MIF is mostly produced
by monocytes, T cells, and the activated endothelium. The project is based on our surprising
observation that thrombocytes, for which a critical
pro-atherogenic role, including the production and
secretion of certain atherogenic chemokines has
been known, contain significant amounts of MIF.
The hypothesis therefore was that platelet-derived
MIF is released upon atherogenic stimulation to
substantively contribute to the developing atherogenic process.
First experiments performed within K5 show that
pure human platelet preparations (‚leukocyte-free
platelet-rich plasma“) are able to specifically secrete MIF upon thrombogenic stimulation (Figure
1). Future studies will address other, pro-atherogenic, stimuli as well as the functional aspects of
platelet-derived MIF in atherosclerotic processes
by both in vitro methods and in mouse models in
vivo (i.e. capitalizing on a Pf4-Cre x Mif-/- mouse).
Publications
IZKF relevant, project associated
1. Kraemer S, Weber C, Bernhagen J (2011) MIF
and the chemokine axis; in: The MIF Handbook,
chapter I-2; World Scientific Press; in press
2. Bernhagen J, Schober C (2011) MIF antagonism as a therapeutic approach to atheroscle-
rosis; in: Advances in Atherosclerosis: Treatment and Prevention. Novel Strategies for the
Treatment of Atherosclerosis, chapter 2; Pan
Stanford Publishing Pte. Ltd.; in press
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
60
Bernhagen, J.
MIF and CXCR2 in liver fibrosis
within SFB-TRR “Organ fibrosis”
DFG
SFB-TRR57
Project P07
01/200912/2012
€ 350,000
Bernhagen, J.
(Liehn, E.)
Structural and functional characterization of MIF/ Chemokine receptors
axis in atherisclerosis and myocardial infarction
DFG
BE 1977/4-2
TP1/DFGFOR809
07/201006/2013
€ 344,400
Rassaf, T.
Bernhagen, J.
Interaction between MIF and nitrite
in myocardial infarction
DFG
Ra969/5-1
07/200906/2012
€ 43,000*
IZKF Aachen Progress Report 2011
Project Funding
|
Cardiovascular Research
|
K5
2.2.
IZKF Aachen Progress Report 2011
61
Funding period: 01.07.2011 - 30.06.2014
Staff: ¾ TV-L 8 (Hoch B.)
SHK (Tenhaes N., Nasrallah H.)
Materials/Travel expenses 2011: € 6,500
Investments/Equipment 2011: –
Bernhagen, J.
Regulation of NFgB/RelA activation DFG
by MIF/CD74 and crosstalk with the SFB-TRR116
CXC chemokine receptor axis
Project A5
within SFB-TRR116 “Signal
integration, crosstalk mechanisms
and networks in inflammatory
cytokine function”
Applied
for:
07/201206/2016
Applied for:
€ 310,000
SFB & project positively
reviewed on
1.2.2012; DFG
“Bewilligungsausschusssitzung”
in May 2012
Kraemer, S.
Bernhagen, J.
Novel anti-chemokine therapeutics
for inflammatory diseases and
cancer
Applied
for:
01/201312/2015
Applied for:
€ 1,845,000
Review decisions
in March 2012 (1st
round) and July
2012 (final round)
Bernhagen, J.
Hackeng, T.
(CARIM,
Maastricht)
et al.
Intervention and imaging in arterial DFG
remodelling: underlying mechanisms IRTG1508/2
and translational strategies
renewal application for 2nd
funding period
Applied
for:
04/201309/2017
Applied for:
€ 2,500,000**
On-site review in
July 2012
BMBF
Go-BIO
program Az
010131P7493
* Part Bernhagen only
** Bernhagen, J. is Spokesman of IRTG1508 and project head in 1 project (PhD5: ca. € 30,000) and co-project head
in 2 projects (PhD7, PhD8: ca. 2x € 15,000 = € 30,000)
Promoting of young researcher
Doctoral Theses
Kanzler, I.
Ongoing
RWTH Aachen,
Faculty 1
Therapeutic potential of MIF in angiogenesis:
novel insights and comparison with established
angiogenic factors
Strüßmann, T.
Ongoing
RWTH Aachen,
Medical Faculty
Activation of MIF secretion from platelets by
thrombogenic stimuli
Wirtz, T.
Ongoing
RWTH Aachen,
Medical Faculty
Role of platelet MIF in atherosclerosis
Postdoctoral lecture qualification
El Bounkari, O.
Ongoing
RWTH Aachen
Physiology and pathophysiology of MIF receptor
complexes (tentative title)
v. Hundelshausen, P.
Ongoing
LMU Munich
Thrombogenic chemokines (tentative title)
Simons, D.
Ongoing
RWTH Aachen, CXCR4-based recruitment and metastasis
DKFZ Heidelberg processes (tentative title)
Awards
Simons, D.: Grünenthal award of the Medical Faculty of RWTH Aachen for the best clinical-theoretical
dissertation 2011
2.2.
Project Funding
|
Cardiovascular Research
|
K6
Funding period: 01.07.2011 - 30.06.2014
Staff: TV-L 7 (Jaskolka, A.)
TV-L 13/2 (Kaesler, N.)
Materials 2011: € 17,500
Investments/Equipment 2011: –
Proatherogenic Effects of C-Peptide in Chronic Kidney
Disease
Burgmaier M. (Department of Internal Medicine I)
Krüger T. (Department of Internal Medicine II)
Part 1: Investigation of the effects of c-peptide on atherogenesis in ApoE-/- mice with and
without chronic kidney disease:
The surgical technique of unilateral nephrectomy initially intended in the proposal had to be
switched to another method to induce chronic
kidney failure as results with the former method
did not show a sufficient increase in kidney parameters. The method we aim to apply is the
electrocauterization model in which using a twostep procedure first one kidney surface is being
cauterized and two weeks later contralateral nephrectomy is performed.
Part 2: Investigation of the effects of c-peptide and chronic kidney disease on vascular
cells in vitro:
Peripheral blood mononuclear cells (PBMCs):
PBMCs were isolated from human buffy coats
and an in vitro cell migration assay in the modified Boyden chamber was performed. The differences between groups are non-significant so far
due to the small number per group (n = 3).
Vascular aortic smooth muscle cells (VSMCs): A
calcification assay from isolated murine VSMCs
62
IZKF Aachen Progress Report 2011
revealed increased calcification due to increased
calcium and phosphate (3 mM) in the cell culture
media. First data show that additional supplementation of C-peptide (1 and 10 nM) do not
show any significant changes in the calcium deposition. Also here, repeated measurements are
necessary.
Part 3: Investigation of the prognostic value
of elevated c-peptide levels in patients with
chronic kidney disease:
The measurements of c-peptide plasma levels
have already been completed in all patients. In
order to correlate c-peptide levels with vascular
calcification and cardiovascular endpoints, c-peptide plasma levels have been measured in both a
cohort of 50 hemodialysis patients, in which cardiac CT-scan has been performed to measure
vascular calcification, as well as in a large cohort
of hemodialysis patients (n=464) in which cardiovascular endpoints have been recorded. Statistical analyses are currently being performed.
2.2.
IZKF Aachen Progress Report 2011
63
PROJECT FUNDING
Clinical Neurosciences
In 2011, the IZKF funded 21 projects with € 651,218 in the research focus area
Clinical Neurosciences.
2.3.
Project Funding
|
Clinical Neurosciences
PROJECT FUNDING
Clinical Neurosciences
FINAL REPORTS
N1 | JOINT RESEARCH PROJECT Weis | 01.07.2008 - 30.06.2011
Cellular and molecular pathogenesis of motor neuron degeneration
p. 68
N1-1 | Weis | 01.07.2008 - 30.01.2013
Studies on the role of axonal transport in the pathogenesis of ALS
p. 69
N1-2 | Beyer | 01.07.2008 - 30.06.2011
Molecular mechanisms of gender differences in amyotrophic lateral sclerosis
p. 71
N1-3 | Lüscher | 01.07.2008 - 30.06.2011
Function and regulation of the NAD+-dependent deacetylase SIRT2 during
the degeneration of motoneurons
p. 73
N1-4 | Zerres | 01.07.2008 - 30.06.2011
Identification and characterisation of motor neuron disease genes
p. 74
N2 | JOINT RESEARCH PROJECT Konrad | 01.07.2008 - 30.06.2011
Neural correlates of interpersonal communication and its disturbances
p. 76
N2-1 | Konrad | 01.07.2008 - 30.06.2011
Neural correlates of expressed emotions in mother-child interactions
p. 77
N2-2 | Huber | 01.07.2008 - 30.06.2011
Neural substrates of turn taking and its disorders
p. 79
p. 82
N2-3 | Mathiak | 01.07.2008 - 30.06.2011
Neural correlates of speech-gesture interaction in interpersonal communication
66
N2-4 | Mathiak | 01.07.2008 - 30.06.2011
Dynamics of the mirror neuron system during social interactions measured
with magnetoencephalography
p. 84
N2-5 | Willmes | 01.07.2008 - 30.06.2011
The processing of verbal and nonverbal cues in arithmetic word problems
p. 86
N2-6 | Habel | 01.07.2008 - 30.06.2011
Cerebral correlates of emotional mimic processing in social situations
functioning as empathy cues
p. 88
IZKF Aachen Progress Report 2011
Project Funding
N3 | Gauggel | 01.07.2008 - 30.06.2011
How the world is represented in the brain? Neural correlates of multimodal
semantic priming in healthy control subjects and patients with panic disorder
|
Clinical Neurosciences
2.3.
p. 90
PROGRESS REPORTS
p. 92
N4 | JOINT RESEARCH PROJECT Habel | 01.07.2011 - 30.06.2014
Impulsivity and Aggression
N4-1 | Konrad/Vloet | 01.07.2011 - 30.06.2014
Neurobiological and neurocognitive indicators of aggressive behaviour in
preschoolers
p. 93
N4-2 | Mathiak/Zepf | 01.07.2011 - 30.06.2014
Genetic-pharmacological imaging of the serotonergic system in violent video games
p. 95
N4-3 | Wiesmann | 01.07.2011 - 30.06.2014
Aggression in the context of situational stimuli
p. 96
N4-4 | Habel/Reetz | 01.07.2011 - 30.06.2014
Impulsivity and aggression in borderline personality disorder and Huntington’s
disease
p. 97
N4-5 | Mottaghy/Vernaleken | 01.07.2011 - 30.06.2014
Context-sensitive influence of MAOA-Genotype on dopaminergic mechanisms
of antisocial behavior and aggression
p. 98
p. 99
N5 | JOINT RESEARCH PROJECT Weis | 01.07.2011 - 30.06.2014
Molecular and cellular mechanisms of degenerative axonopathies
N5-1 | Falkenburger/Schulz | 01.07.2011 - 30.06.2014
Dynein-mediated transport and clearance of protein aggregates
p. 100
N5-2 | Lüscher | 01.07.2011 - 30.06.2014
Control of protein aggregation and autophagy by SIRT2
p. 101
N5-3 | Weis | 01.07.2011 - 30.06.2014
Degenerative axonopathy of skin nerve fibers in Parkinson’s disease,
Amyotrophic Lateral Sclerosis and in axonal Charcot-Marie-Tooth neuropathy
p. 102
N5-4 | Rudnik-Schöneborn/Glas | 01.07.2011 - 30.06.2014
Identification and characterization of novel genes for hereditary axonopathies
p. 104
N6 | Gründer | 01.07.2011 - 31.12.2012
Acid-sensing ion channels (ASICs) and the pathophysiology of hepatic
encephalopathy
p. 106
IZKF Aachen Progress Report 2011
67
2.3.
Project Funding
|
Clinical Neurosciences
|
N1
Funding period: 01.07.2008 - 30.06.2011
Materials 2011: € 33,500
Investments/Equipment 2011: –
Cellular and molecular pathogenesis of motor neuron
degeneration
Weis J. (Department of Neuropathology)
Motor neuron diseases (MNDs) are characterized
by a selective degeneration of motor neurons.
Amyotrophic lateral sclerosis (ALS) affects the
first and second motor neuron and is one of the
most frequent and devastating neurodegenerative diseases. Approximately 10% of ALS cases
are familial. Spinal muscular atrophies (SMAs)
are caused by gene defects in most cases and
selectively affect the second motor neuron. Our
collaborative project is focused on the molecular
genetic analysis of hereditary cases of MNDs,
the neuropathological examination of ALS and
MND tissues and cell and molecular biological
studies using in vitro and in vivo models to study
the effects of alterations of intracellular transport,
oxidative metabolism and of growth factor and
hormone functions in motor neuron diseases.
During the funding period, we established several cell culture and animal models of MNDs and
extended our collection of tissues (autopsy mate-
68
IZKF Aachen Progress Report 2011
rial, nerve, muscle and skin biopsies, fibroblast
and lymphoblast cultures) and DNAs of MND
cases in the framework of the UKA biobank and
of the German Motor Neuron Disease Tissue
Bank, both funded by the BMBF.
In 2010, we filed an application to the German
Research Council (DFG) for funding of a Clinical Research Group focused on neuromuscular
disorders. This application was rejected, but the
DFG acknowledged the expertise of the Aachen
group in this field and encouraged resubmission.
We decided to improve the base for such an application by focusing on axonal changes, including aspects of CNS neurodegeneration. Thus, we
submitted the collaborative proposal “Molecular
and cellular mechanisms of degenerative axonopathies”, which gained approval by the IZKF
(see project N5).
Project Funding
|
Clinical Neurosciences
|
N1-1
2.3.
Funding period: 01.07.2008 - 30.01.2013
Staff: TV-L 13 (Goswami A.)
Materials 2011: € 9,000
Investments/Equipment 2011: –
Studies on the role of axonal transport in the pathogenesis of ALS
Weis J. (Department of Neuropathology)
In order to investigate the potential involvement
of the small sensory fibers of the epidermis in
the neurodegenerative process of Amyotrophic
Lateral Sclerosis (ALS) we evaluated the intraepidermal nerve fiber density (IENFD) of 28
ALS patients and an age matched control group
of 17 healthy individuals. We found a significant
reduction in ENFD in the distal calf of patients
with ALS (4.8 +/- 3.7 fibers/mm vs. 12.2 +/- 4.6 in
age-matched controls, p=0.0001). The epidermal
nerve fiber loss in patients with ALS increased
with age. This could be due to an additive effect
of a modest age-related decrease of skin innervation, which was observed previously. However,
this does not occur in the age-matched control
group. Also, the num-ber of subjects with small-fiber neuropathy was significantly higher in the ALS
group than in the controls (79% vs. 12%, threshold=8 fibers/mm, p<0,001). Proximal (thigh) epidermal nerve fibers were only marginally affected
at the most, whereas distal (calf) axons were
considerably and significantly reduced in patients
with ALS (proximal: 8.2+/- 4.6 fibers/mm; distal:
4.8+/-3.7 fibers/mm). Correspondingly, mild sensory symptoms including diffuse dysesthesias,
paresthesias, and hypesthesia were found in 7
patients. Patients who re-ported minor symptoms of sensory involvement of the distal lower
leg were more severely affected by epidermal
nerve fiber loss. In 17 biopsies of patients with
ALS, but only in 2 con-trols, we saw larger (1.5
m in diameter) focal swellings of epidermal axons
resembling sphe-roids, suggesting trafficking
defects. This data has been presented and published by our group (Weis et al. Neurology 2011;
76; 2024). Our current goal is the identification of
the nature of these swellings, for which we are
performing immunohistochemistry with antibodies against markers of the axonal transport system and the protein degradation machinery. We
also investigate the changes in these fibers in a
project where in a similar fashion we look at skin
biopsies of patients with Parkinson’s disease and
REM sleep behavioural disor-der, which is known
to be associated with various neurodegenerative
diseases (Parkinson’s disease, Alzheimer’s disease, dementia). We expect the changes in the
peripheral sensory fibers to also be an early sign
of neurodegeneration in these cases.
Figure 1: Reduction in epidermal nerve fiber (arrows) density in
ALS patient skin (b) com-pared to control (a) and focal swellings of
epidermal axon (inset in b). Cryostat sections, PGP9.5 immunohistochemistry.
Publications
IZKF relevant, project associated
1. Weis J*, Katona I*, Müller-Newen G, Sommer
C, Necula G, Hendrich C, Ludolph AC, Sperfeld A-D. Small fiber neuropathy in ALS pa-
tients. Neurology. 76(23): 2024-9, 2011 *Equal
contribution. [IF 8,0]
IZKF Aachen Progress Report 2011
69
2.3.
Project Funding
|
Clinical Neurosciences
|
N1-1
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Weis, J.
Goswami, A.
Consequences of VAPB mutation in the Deutsche
pathogenesis of ALS8
Gesellschaft für
Muskelkranke
(DGM)
7/2010- € 30,000
6/2012
Weis, J.
Krüttgen, A.
Zerres K.
Pathogenesis of hereditary sensory
DFG; WE
and motor neuropathies: Integrating
1406/13-1
neuropathology and molecular genetics
20102013
Weis, J.
Kretzschmar
(München)
Thal (Ulm)
The German MND Tissue Bank
3/2012- € 120,000
2/2015
BMBF 120203
€ 400,000
Promoting of young researcher
Diploma Theses
Buchkremer, S.
Ongoing
RWTH Aachen,
Faculty 1
Identification of new factors from the SIL1
interactome
Bauschulte, J.H.
Ongoing
RWTH Aachen, Effects of lysophosphatic acid on nerve growth
Faculty of Medicine factor and tropomyosin-related kinase A receptor
signal transduction
Meinhardt, A.
Ongoing
RWTH Aachen, Genotype-phenotype correla-tion in neuropathies
Faculty of Medicine due to MPZ mutation
Katona, I.
Ongoing
RWTH Aachen, Pathogenesis of HSANs
Faculty of Medicine
and Faculty 1
Wagner, S.
Ongoing
RWTH Aachen, ALS: Clinico-neuropathological correlations
Faculty of Medicine
Bushuven, E.
Ongoing
RWTH Aachen, VAPB in the pathogenesis of ALS
Faculty of Medicine
Nikolin, S.
Ongoing
RWTH Aachen, Patterns of characteristic muscle fiber alterations
Faculty of Medicine in ALS
Doctoral Theses
Postdoctoral lecture qualification
Claeys, K.
70
IZKF Aachen Progress Report 2011
2011
RWTH Aachen, Clinico-pathological characterization and genotypeFaculty of Medicine phenotype correlations in hereditary neuromuscular
disorders
Project Funding
|
Clinical Neurosciences
|
N1-2
2.3.
Funding period: 01.07.2008 - 30.06.2011
Staff: ½ TV-L 13 (Behrens S.)
½ TV-L 9 (Helten H.)
Materials 2011: € 10,000
Investments/Equipment 2011: –
Molecular mechanisms of gender differences in amyotrophic
lateral sclerosis
Beyer C. (Department of Neuroanatomy)
Arnold S. (Department of Neuroanatomy)
The mitochondrion is the unquestionable cellular
compartment that actively preserves most of the
cell functions, such as lipid metabolism, ion homeostasis, energy and ROS production, steroid
biosynthesis, and control of apoptotic signaling.
Thus, this cell organelle depicts a major drop-in
centre for regulatory processes within a cell irrespective of the organ or tissue. However, brain
tissue is unique in spite of everything due to its
extremely high energy demand and sensitivity to
oxidative stress. This makes brain cells, in particular neurons, considerably vulnerable against
toxins and challenges that attack the mitochondrial structural organization and energetic performance. Estrogens are known to regulate a multitude of cellular functions in neural cells under
physiological conditions but also play a protective role under neuropathological circumstances.
Estrogens indirectly regulate the mitochondrion
through the control of genomic transcription of
mitochondrial-located proteins and modulation
of cytoplasmic signaling cascades that act upon
mitochondrial physiology. More recent data suggest that estrogens might directly signal to the
mitochondrion either through classical steroid receptors or novel types of receptors/proteins associated with the mitochondrial compartment. This
would allow estrogens to more rapidly modulate
the function of a mitochondrion than hitherto discussed. Assuming that this novel perception of
steroid action is correct, estrogen might influence
the energetic control centre through long-lasting
nuclear-associated processes and rapid mitochondria-intrinsic temporary mechanisms.
Our studies clearly show that estrogens regulate the mitochondrial structure and function in
the spinal cord of mice under pathophysiological
conditions similar to amyotrophic lateral sclerosis
(ALS).
Motoneurons located in the ventral horn of the
spinal cord conciliate cholinergic innervation of
skeletal muscles. These neurones appear to be
exceedingly affected in eurodegenerative diseases such as ALS. The dysfunction of motoneurons
is typically accompanied by alterations of cholinergic metabolism and signalling documented by a
decrease in choline acetyltransferase (ChAT) expression. Estrogens appear to exert a protective
role for moto-neurons. In our study, we attempted
to analyze the role of estrogen signalling on ChAT
expression in the motoneuron-like cell line NSC34 and in vivo. In a first step, we demonstrated
the presence of estrogen receptor (ER) alpha
and beta in NSC-34 cells as well as in the cervical and lumbar parts of the male mouse spinal
cord. Subsequently, we investigated the effect of
estrogen treatment on ChAT expression. The application of estrogens significantly increased the
transcription of ChAT in NSC-34 cells and in the
cervical but not lumbar part of the spinal cord.
Our results indicate that estrogens can influence
the cholinergic system by increasing ChAT expression in the mouse spinal cord. This mechanism might support motoneurons, in addition to
survival-promoting mechanisms, to temporarily
balance toxic or neuro-degenerative challenges.
Publications
IZKF relevant, project associated
1. Boyalla S, Victor MB, Roemgens A, Beyer C,
Arnold S (2011) Sex- and brain region-specific
role of cytochrome c oxidase in 1-methyl-4-
phenylpyridinium-mediated astrocyte vulnerability. J Neurosci Res 89:2068-2082 [IF 2.9]
2. Johann S, Dahm M, Kipp M, Zahn U, Beyer C
IZKF Aachen Progress Report 2011
71
2.3.
Project Funding
|
Clinical Neurosciences
|
N1-2
(2011) Regulation of ChAT expression by oestrogen in NSC-34 cells and in the spinal cord.
J Neuroendocrinol 23:839-848 [IF 4.7]
3. Roemgens A, Misiak M, Beyer C, Arnold S
(2011) Inducers of chemical hypoxia act in a
gender- and brain region-specific manner on
primary astrocyte viability and cytochrome c
oxidase. Neurotox Res 20:1-14 [IF 3.0]
4. Arnold S, Viktor MB, Beyer C (2012) Estrogen
and the regulation of mitochondrial structure
and function. J Steroid Biochem Mol Biol in
press [IF 2.9]
Promoting of young researcher
Diploma Theses
Hymes, H.
2011
RWTH Aachen,
Medicine
The influence of amyloid-beta protein on the
expression of cytochrome c oxidase isoforms
Schmitz, S.
2011
RWTH Aachen,
Medicine
Isoform expression of cytochrome c oxidase
subunits and its influence on mitochondrial
function
Römgens, A.
Ongoing
RWTH Aachen,
Medicine
Chemical hypoxia shows sex- and brain-region
specific differences of astrocyte survival and
transcription of cytochrome oxidase subunit IV
Doctoral Theses
72
IZKF Aachen Progress Report 2011
Project Funding
|
Clinical Neurosciences
|
N1-3
2.3.
Funding period: 01.07.2008 - 30.06.2011
Staff: ½ TV-L 13 (Flick F.)
½ TV-L 9 (Helten H.)
Materials 2011: € 8,000
Investments/Equipment 2011: –
Function and regulation of the NAD+-dependent deacetylase
SIRT2 during the degeneration of motoneurons
Lüscher B. (Department of Biochemistry and Molecular Biology)
Neurodegenerative processes are associated
with the accumulation of aggregates of misfolded
proteins, which is closely linked to cellular stress.
Inadequate processing of protein aggregates,
e.g. by the autophagosomal or by the ubiquitinproteasomal system, is critical for the phenotype
because these aggregates affect normal physiological protein turnover and intracellular transport
processes. Both are regulated by posttranslational
modifications including acetylation. We wanted
to address the functional relevance of the CDK5SIRT2-HDAC6 regulatory network for protein
aggregation and neurotoxicity. Therefore we finished the evaluation of newly generated mAbs (in
cooperation with Dr. Elisabeth Kremmer, Munich)
against SIRT2 C-terminal peptides phosphorylated
at Ser-331 and/or Ser-335. We selected mAbs that
specifically recognize all different isoforms of C-terminally phosphorylated SIRT2 in immunoblotting
and immunofluorescence experiments. With these
reagents we will be in the position to measure the
phosphorylation status of SIRT2 under different
physiological conditions.
Furthermore we identified GCN5 as a lysine-specific acetyltransferase that targets CDK5 as well
as SIRT2 in vitro and in cells. GCN5 thus provides
another level of complexity in the CDK5-SIRT2HDAC6 regulatory network.
Figure 1: Acetylation of CDK5 and CDK5 mutants after co-expression
of GCN5. HEK293 cells were transiently transfected with expression
plasmids as indicated. After 48 hours cells were harvested and lysed
in CoIP-buffer containing deacetylase inhibitors. CDK5 was immunoprecipitated with a tag-specific antibody. Immunoprecipitates (IP) and
whole cell lysates (WCL) were subjected to SDS-PAGE and Western
blot. Acetylated CDK5 was detected with an antibody specific for acetylated lysines. Tubulin detection served as a loading control.
Publications
IZKF relevant, project associated
1. Flick F, Lüscher B (2012) Regulation of sirtuin function by posttranslational modifications.
Front Pharmacol. 3:29
Promoting of young researcher
Bachelor Theses
Schall, N.
2011
RWTH Aachen, Regulation of the p35/CDK5 kinase complex and
Institute of
its role in controlling SIRT2 in melanoma
Biochemistry and
Molecular Biology
Ongoing
RWTH Aachen, Regulation of the NAD+-dependent deacetylase
Institute of
SIRT2 by CDK5
Biochemistry and
Molecular Biology
Doctoral Theses
Flick, F.
IZKF Aachen Progress Report 2011
73
2.3.
Project Funding
|
Clinical Neurosciences
|
N1-4
Identification and characterization of genes for motor neuron
disorders
Zerres K. (Institute of Human Genetics)
The goal of this project is the identification of
genes involved in monogenic forms of motor
neuron disorders (NMD). Methodologically, we
investigate affected families by genome-wide single nucleotide polymorphism (SNP) genotyping
and DNA sequencing. In case of positive results,
we validate and extend our findings in independent cohorts presenting with these conditions. If
time permits, we also investigate the aetiology
of NMD by functional analyses of the identified
gene products, by using cellular and molecular
assays, banked tissue samples, and animal models accessible through the other subprojects. We
have identified the causative gene mutation in a
particular family with autosomal recessive motor
neuron disorder combined with congenital cataracts. Following genome wide linkage analysis,
we analysed the SYNE1 gene which resided in
one of the few remaining regions of interest. Affected patients were found to be homozygous for
a truncating SYNE1 mutation that segregated
with the disease according to an autosomal re-
cessive disorder (manuscript in preparation). We
have also investigated the genetic defects in a
cohort of patients with hereditary motor neuropathy (HMN) with predominant involvement of the
hand muscles (HMN V, Silver-syndrome). Most
of these patients were found to carry mutations
in the GARS and BSCL2 genes which had been
linked to this condition earlier. In order to identify
the genetic causes in four pedigrees without mutations in the GARS and BSCL2 gene, we have
started a collaborative study with Prof. M. AuerGrumbach (Graz) who has an extended collection of unclassified HMN V patients. Finally, we
have expanded the phenotype associated with
SETX mutations to include autosomal dominant
spinal muscular atrophy (Rudnik-Schöneborn et
al., 2011) and contributed to the discovery of a
new gene for inherited neuropathies (Auer-Grumbach et al., 2011) and a methodological paper
presenting an effective approach for a molecular
diagnosis in autosomal recessive hereditary neuropathies (Fischer et al., 2011).
Publications
IZKF relevant, project associated
1. Auer-Grumbach M, Weger M, Fink-Puches
R, Papić L, Fröhlich E, Auer-Grumbach P, El
Shabrawi-Caelen L, Schabhüttl M, Windpassinger C, Senderek J, Budka H, Trajanoski S,
Janecke AR, Haas A, Metze D, Pieber TR,
Guelly C. Fibulin-5 mutations link inherited
neuropathies, age-related macular degeneration and hyperelastic skin (2011) Brain
134:1839-52. [IF 9,23]
2. Fischer C, Trajanoski S, Papić L, Windpassinger C, Bernert G, Freilinger M, Schabhüttl
M, Arslan-Kirchner M, Javaher-Haghighi P,
74
IZKF Aachen Progress Report 2011
Plecko B, Senderek J, Rauscher C, Löscher
WN, Pieber TR, Janecke AR, Auer-Grumbach
M (2011) SNP array-based whole genome
homozygosity mapping as the first step to a
molecular diagnosis in patients with CharcotMarie-Tooth disease. J Neurol DOI: 10.1007/
s00415-011-6213-8. [IF 3,85]
3. Rudnik-Schöneborn S, Arning L, Epplen JT,
Zerres K (2011) SETX gene mutation in a family diagnosed autosomal dominant proximal
spinal muscular atrophy. Neuromuscul Disord
DOI: 10.1016/j.nmd.2011.09.006. [IF 2,62]
Project Funding
|
Clinical Neurosciences
|
N1-4
2.3.
Funding period: 01.07.2008 - 30.06.2011
Staff: TV-L 9 (Diepolder I.)
Materials 2011: € 6,500
Investments/Equipment 2011: –
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Weis, J.
Krüttgen, A.
Zerres, K.
Pathogenesis of hereditary sensory
DFG; WE
and motor neuropathies: Integrating
1406/13-1
neuropathology and molecular genetics
20102013
€ 400,000
Rivolta
Senderek
Chrast
Gene hunting for recessive
peripheral neuropathies by recent and
highly-parallel technologies
Gebert-RüfStiftung, Basel
07/201006/2013
€ 255,000
own part:
€ 102,000
Senderek, J.
Heisenberg-Stipendium
DFG - Se
1839/1-1
09/200808/2011
€ 160,000
Promoting of young researcher
Appointments to other universities
Senderek, J.
Ludwig-Maximilians-University, Munich
W2
accepted
IZKF Aachen Progress Report 2011
75
2.3.
Project Funding
|
Clinical Neurosciences
|
N2
Funding period: 01.07.2008 - 30.06.2011
Staff: ½ TV-L 13 (Pohl, A.)
Materials 2011: € 2,800
Investments/Equipment 2011: –
Neural correlates of interpersonal communication and its
disturbances
Konrad K. (Department of Child and Adolescent Psychiatry and Psychotherapy)
Huber W. (Department of Neurology)
Habel U. (Department of Psychiatry and Psychotherapy)
In the collaborative project ‘Neural correlates of
interpersonal communication and its disturbances’ we examined interpersonal interactions with
functional imaging methods like fMRI or MEG.
We studied healthy participants as well as patients with major depression, schizophrenia and
autism, including both samples with children as
well as adults. We successfully developed experiments which incorporate natural interactive
situations proving them more ecologically valid.
The research projects published initial results
providing new insights into multimodal integra-
tion, impact of verbal cues on solving arithmetic
word problems, and the emotional mirror neuron
system.
In 2011, a workshop on “The exbodied mind – motion communication and cognition research” was
organized by the collaboration projects together
with the Humtec Natural Media & Engineering
group. This workshop included lectures given by
international speakers and researchers involved
in N2, as well as a poster session. The workshop
was supported by funds from RWTH Aachen interdisciplinary fora.
Publications
IZKF relevant, project associated
1. Greimel E, Schulte-Rüther M, Kamp-Becker I,
Remschmidt H, Herpertz-Dahlmann B, Konrad
K. [Self-report and parental report of empathy
in adolescents with autism]. (2011) Z Kinder
Jugendpsychiatr Psychother 39:113-21.[IF:
0,717]
2. Kircher, T.*, Pohl, A.*, Krach, S., Thimm, M.,
Schulte-Rüther, M., Anders, S., Mathiak, K.
(in press) (2012) Affect-Specific Activation of
Shared Networks for Perception and Execution of Facial Expressions. Social Cognitive
and Affective Neuroscience [IF 4.482]
* contributed equally
Promoting of young researcher
Doctoral Theses
Pohl, A.
76
IZKF Aachen Progress Report 2011
Ongoing
RWTH Aachen,
Dept. of
Psychiatry,
Psychotherapy
and Psychosomatics
Mirror Neurons and Imitation of Dynamic Facial
Expressions: An fMRI Study
Project Funding
|
Clinical Neurosciences
|
N2-1
2.3.
Funding period: 01.07.2008 - 30.06.2011
Staff: TV-L 13 (Greimel E., Pütz V.,
Thönnessen H., von Polier G.)
Materials 2011: –
Investments/Equipment 2011: –
Neural correlates of expressed emotions in mother-child
interactions
Konrad K. (Department of Child and Adolescent Psychiatry and Psychotherapy)
Herpertz-Dahlmann B. (Department of Child and Adolescent Psychiatry and Psychotherapy)
In the third year of funding we completed the
second large fMRI study on neural mechanisms
underlying social exclusion in children with early
separation experiences. Early separation experiences can disrupt the child’s attachment process
and interfere with the psychosocial development
of an infant. Specifically, early separation experiences are hypothesized to render these children
more susceptible to social exclusion and rejection, as reflected in differential activation of the
social-pain network including fronto-limbic structures (anterior cingulate, mPFC and hippocampus). We thus investigated 26 children that grew
up with their biological parents and 25 children
with an early parental separation experience with
a social-exclusion paradigm. fMRI data revealed
robust differences in neural activation in response
to social exclusion between the groups. In line
with previous research, the typical “pain matrix”
consisting of the ACC, left and right insulae and
rmPFC was active in our control children. Interestingly, activation in the ACC, which has been
implicated in signalling situations that require
cognitive control, was absent in the ES group,
suggesting an abnormal pain response when facing ostracism. Rather, when facing social threat,
children with ES experience activated brain areas
that are involved in mentalizing, theory of mind
and action understanding (STS/TPJ), as well as
episodic memory (hippocampus). These results
suggest abnormal social brain functioning in children with an early parental separation experience
that could be mediated by impaired PFC-regulation, confirming our hypothesis that early separation has a long-lasting effect on children’s neuronal functioning.
Figure 1: Neural mechanism underlying social exclusion after early
separation experiences
Publications
IZKF relevant, project associated
1. Greimel E, Schulte-Rüther M, Kamp-Becker I,
Remschmidt H, Herpertz-Dahlmann B, Konrad
K. [Self-report and parental report of empathy
in adolescents with autism]. (2011) Z Kinder
Jugendpsychiatr Psychother 39:113-21.[IF:
0,717]
IZKF Aachen Progress Report 2011
77
2.3.
Project Funding
|
Clinical Neurosciences
|
N2-1
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Schneider, F.
(Spokesman)
International Research Training
Group 1328: Brain-behavior
relationship of emotion and social
DFG
2010(submitters: Amunts, 2014
Eickhoff, Feldmeyer,
Gründer, Habel,
Herpertz-Dahlmann,
Kobbelt, Konrad,
Lübke, Mathiak,
Shah, Willmes)
IRTG 1328
€ 2.1 M
Konrad
Bilateral collaboration
DFG
20102011
€ 22,100
Konrad
Long-term Safety of MPH
EU
20102015
€ 320,000
HerpertzDahlmann &
Konrad
Behavioural, developmental and
neural effects of a standardized
mother-child intervention
programme in adolescent mothers
and their children
BMBF
20122015
€ 256,440
HerpertzDahlmann &
Konrad
Neuropsycholocial functioning and
structural and functional brain
abnormalities in Anorexia nervosa
before and after treatment
BMBF
20072012
Promoting of young researcher
Diploma theses
Zweerings, J.
Ongoing
Maastricht,
Faculty of
Psychology
Neuroendocrine stress-responses to social
rejection in a sample of children with early
separation experiences
Ongoing
Maastricht,
Faculty of
Psychology
Assessing behavioral problems in children in care
Doctoral Theses
Ruf, C.
78
IZKF Aachen Progress Report 2011
Project Funding
|
Clinical Neurosciences
|
N2-2
2.3.
Funding period: 01.07.2008 - 30.06.2011
Staff: TV-L 13 (Klann J.)
SHK (Wegner A.)
Materials 2011: –
Investments/Equipment 2011: –
Neural substrates of turn taking and its disorders
Huber W. (Department of Neurology)
Konrad K. (Department of Child and Adolescent Psychiatry and Psychotherapy)
Mathiak K. (Department of Psychiatry and Psychotherapy)
Turn-taking is seen as a basic mechanism of the
The main effects of the dialogue condition reveal
human ability to communicate and participate in
activations within the whole network of social indialogues. It is marked by verbal and nonverbal
teraction (cf. fig. 1, middle). A contrasting, subcues. So far, the neural substrates remain untracting monologue from the dialogue condition
clear, since studies that investigate dyadic comresults in activation of some smaller parts of this
munication directly and online, are still missing.
network as being typically relevant for dyadic
From reviews of classic fMRI studies, hypotheses
communication when taking the turn (cf. fig. 1,
were derived along a model of social interaction
right side). These regions were formerly associ(cf. fig. 1, right side; Hari & Kujala 2009).
ated with functions of context integration, inferIn our study, 12 single male participants between
ences, awareness, episodic memory retrieval
20 and 40 years of age were
scanned while they were interviewed about their life history by
a person outside the MR-scanner.
Communication was transferred
with the help of a webcam and a
headset, such that the person in
the MR-scanner could see and
hear the interviewer during the
interview. In order to control for
effects of mere talking/starting
to talk without communicative
impact, a control condition was
conducted prior to the interview.
Here, the participant had to tell his
life history as an autobiographical
monologue. From time to time he
was interrupted by a visual stopsignal and unintelligible speech.
This should simulate the interview
structure to parallel the number of
mere speak starts with the number
of turns in the interview condition.
Statistical parametric data analyses were executed with SPM8. After outsourcing backchannels (utterances that do not initiate a new
turn, like affirmative “hmhm” etc.),
the time-points, when the particiFigure 1: Results of time-locked efMRI analyses (left side: model of hypothesized netpant started to talk, were defined
work of social interaction derived from several classic fMRI studies as presented in Hari
as events for a time-locked event& Kujala, 2009; middle: local activation maxima for the dialogue condition; right side:
local activation maxima for the contrast dyadic dialogue – monologue)
related analysis.
IZKF Aachen Progress Report 2011
79
2.3.
Project Funding
|
Clinical Neurosciences
|
N2-2
and ToM (Hari & Kujala 2009, van Overwalle
2009, Northoff & Bermpohl 2004, MacGuire et
al. 1999). This is the first study that gives direct
evidence for communicative functions being represented within a more general cognitive network
of social interaction.
Publications
IZKF relevant, project associated
1. Klann J, Huber W (2011): Situationsmodell
und narrative Shifts: Voruntersuchungen zur
Diagnostik von sprachlichen und kognitiven
Verstehensproblemen bei hirngeschädigten
Patienten. Sprache Stimme Gehör 35:26-31
[IP: 0,172]
2. Klann J (in press): Psycholinguistik und Neurolinguistik der Gebärdensprachen. In Heßmann
J, Eichmann, H. & Hansen M (eds.): Handbuch der Gebärdensprache. Hamburg: Signum.
(article in monography)
3. Klann, J (2011): Verstehen sie Sprache ... in
Gebärden auch mit links? In: Folger-Fonfara
S, Klidis-Honecker A & A Speer (Hrsg.): Anthropologie, Rezeption, Transkulturation, Episteme, Sprache - Jahrbuch der a.r.t.e.s. Forschungsschule. Köln: Flyeralarm (Universität zu
Köln): 78-82 (article in monography)
4. Klann, J (accepted): Zur Rolle der Ikonizität
in Gebärdensprachen untersucht am Beispiel
der deutschen Gebärdensprache. Berlin: Mouton de Gruyter (monography)
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
80
Binkofski (Head
of transnational
researchgroup
and project
executed in
Aachen;
invovlvement
of N2-2 postdoc
J. Klann)
Cognitive recovery after stroke. EraNet/EU
Translational approach to new
BMBF
therapies of higher motor deficits
(COGSTROKE)
04/201203/2015
Binkofski
Klann, J.
Through the looking glass:
Entwicklung und Erprobung
einer neuen Spiegeltherapie zur
Rehabilitation bei Aphasie und
Apraxie
DFG
in prep.
Mittelberg
Huber, W.
Klann, J.
Habel, U.
The neural substrate of emotional and linguistic mimic in German
Sign Language (Neurale Substrate emotionaler und sprachlicher Mimik in der Deutschen
Gebärdensprache)
DFG (TP of the
DFG-Forschergruppe “Nonmanuals in sign
languages“;
Heads: Prof. Dr.
phil. M. Steinbach, Göttingen
& Prof. Dr. phil.
D. Adone, Köln)
“Forschergruppe”
rejected; project
from Aachen
rated high =>
proposal for
single proposal
in preparation
(DFG)
Jäger
Huber, W.
Willmes-von
Hinckeldey, K.
AILB III: Vibelle-Info 2.0 und
Vibelle–elearning 2.0 (Aachener
Internet-Lernsoftware zur Berufsqualifizierung von Gehörlosen)
Bundesministeri- 05/2009um für Gesund- 04/2012
heit und soziale
Sicherung
IZKF Aachen Progress Report 2011
€ 1,250,000
(Aachen: ca.
€ 300,000)
€ 875,200
Project Funding
|
Clinical Neurosciences
|
N2-2
2.3.
IZKF Aachen Progress Report 2011
81
Promoting of young researcher
Diploma theses
Kelke, J.
Ongoing
RWTH Aachen,
Logopedics
The effect of getsures on lexical retrieval in aphasia
Haber, E.-M.
Ongoing
RWTH Aachen,
Logopedics
Naming in aphasia and sound: Development of a
naming test with the help of sounds
Kuhnert, S.
Ongoing
Universität
zu Köln,
Linguistik
Thinking and Speaking: Investigating the
correlation of linguistic and other cognitive mental
processes in aphasia: a single case study
Schlapka, M.
Ongoing
FriedrichPhonetic skills in a single case of early cochlea
Wilhelmsimplantation: a longitudinal study
Universität, Bonn
Byell, L.
Schultze, J.
Ongoing
NL: Faculteit
Logopedie,
Hogeschool
Zuyd, Heerlen
Reading and writing skills in hearing Children of
deaf adults (CODAs)
Wendland, M.-K. Ongoing
RWTH Aachen,
Logopedics
I Can‘t find the right word - in sentences:
a single case study on therapy of anomia in
complex contexts in childhood aphasia
Eidt, B.
Ongoing
RWTH Aachen,
Logopedics
Gestures in aphasic communication
Marré, H.
Ongoing
RWTH Aachen,
Logopedics
Neurovitalis
Gosewinkel, S.
2011
RWTH Aachen,
Logopedics
Initiation of communicative behaviour and speech
with the help of the „Picture Exchange Communication Systems (PECS)“: a single-case study with
a four year old boy suffering from Dandy-WalkerSyndrome
Hensche, A.
2011
RWTH Aachen,
Logopedics
The transfer of the “Szenario-Test“ into german:
investigation of psychometric parameters for
aphasic patients
Theilmann, A.
2011
RWTH Aachen,
Logopedics
The transfer of the “Szenario-Test“ into german:
investigation of psychometric parameters for
healthy controls
Kawalla, M.
2011
RWTH Aachen,
Logopedics
Evaluation of pragmatic skills with the help of the
“ANELT“ – an empirical study on the effectiveness
of therapy on the “Aachen Aphasia Ward“
Schmidt, F.
2011
Westsächsische
Hochschule
Zwickau
Cerebral Representation of mimical functions in
L1-users of Sign Language
Pockett, A.-J.
2011
RWTH Aachen,
Logopedics
Narrative shifts: comparing reception of silent
movies and texts in german and finnish
2.3.
Project Funding
|
Clinical Neurosciences
|
N2-3
Neural correlates of speech-gesture interaction in interpersonal communication
Mathiak K. (Department of Psychiatry and Psychotherapy)
The integration of emotional cues from speech
and face as well as the underlying neural substrates of the latter have recently attracted attention as markers of social cognition in interpersonal
communication. However, the question whether
perceptual binding of facial and vocal emotions
takes place in primary sensory areas, multimodal
cortices, or in affective structures has remained
unanswered so far. Extending the findings of earlier project stages, the goal of this study was to
reveal the neural structures involved in the processing of audiovisual emotional cues in interpersonal communication. Using novel computergenerated stimuli we combined emotional faces
and voices in congruent and incongruent ways
and assessed functional brain data (fMRI) during
an emotional classification task. Both congruent and incongruent audiovisual stimuli evoked
larger responses in thalamus and superior temporal regions as compared to unimodal conditions. Congruent emotions were characterized by
activation in amygdala, insula, ventral posterior
cingulate (vPCC), temporo-occipital, and auditory
cortices; incongruent emotions activated a frontoparietal network and bilateral caudate nucleus,
Figure 1: Supramodal representation of emotional communication cues
82
IZKF Aachen Progress Report 2011
indicating a greater processing load in working
memory and emotion-encoding areas. The vPCC
alone exhibited differential reactions to congruency and incongruency for all emotion categories
and can thus be considered a central structure
subserving the integration of complex emotional
information. Moreover, the left amygdala reflected a supramodal representation of happy stimuli.
These findings document that emotional aspects
from audiovisual social cues do not converge at
the perceptual audiovisual integration level in unior multimodal areas, but in vPCC and amygdala
(Figure 1).
Project Funding
|
Clinical Neurosciences
|
N2-3
2.3.
Funding period: 01.07.2008 - 30.06.2011
Staff: TV-L 13
(Klasen M., Isman G., Dyck M.)
SHK (Ryszka D., Gröne M., Alawi E.)
Materials 2011: € 500
Investments/Equipment 2011: –
Publications
IZKF relevant, project associated
1. Klasen, M., Weber, R., Kircher, T. T., Mathiak,
K. A. & Mathiak, K. (2011). Neural contributions
to flow experience during video game playing.
Social Cognitive and Affective Neuroscience,
Epub ahead of print. [IF 4.482]
2. Klasen, M., Kenworthy, C., Mathiak, K. A., Tilo,
K. & Mathiak, K. (2011). Supramodal representation of emotions. The Journal of Neuroscience, 31(38), 13635-13643. [IF 7.271]
Promoting of young researcher
Doctoral Theses
Klasen, M.
2011
RWTH Aachen,
Dept. of
Psychiatry,
Psychotherapy
and Psychosomatics
Virtual reality as stimulus material in the social
neurosciences
IZKF Aachen Progress Report 2011
83
2.3.
Project Funding
|
Clinical Neurosciences
|
N2-4
Dynamics of the mirror neuron system during social
interactions measured with magnetoencephalography
Mathiak K. (Department of Psychiatry and Psychotherapy)
The mirror neuron system (MNS) has been revealed as an important network for recogniton
and understanding of voluntary and affective
behaviour of others. Neuroimaging studies demonstrated shared neural patterns during both observation and imitation of facial expressions. Furthermore, a successful social interaction requires
crossmodal integration of communicative social
signals. The intention of the current study was to
investigate brain activation patterns during observation and imitation of facial expressions with
regard to their modality, valence, and sex.
30 (15 male) healthy subjects participated in the
study. Emotional cues with different valence (happy, angry, neutral) and sex (male/female) were
presented in different modalities (auditory, visual,
audio-visual) in a block design. Auditory stimuli
consisted of pseudowords with emotional prosody; visual stimuli consisted of static emotional
face pictures. The participants were required to
either observe or imitate the faces and to rate
their emotional valences per button press. Face
muscle activity during the imitation condition was
quantified using electromyography (EMG).
Similar brain activation patterns were observed in
both conditions, including the inferior and middle
frontal gyrus, insula, superior temporal gyrus,
putamen and thalamus (see Fig.1a). Additionally, in the imitation condition the supplementary
motor area, cuneus, inferior parietal lobule, and
midbrain areas were activated (see Fig.1b). The
angry, compared to the happy, facial expressions
elicited left lateralized enhanced activation in
the superior and middle frontal gyrus, precuneus, cingulate gyrus, inferior parietal lobule, and
claustrum (see Fig.1c).
The results are in accordance with evidence of
previous studies, pointing to shared brain networks during observation and imitation of emotional facial expressions. The observed activation
in the imitation condition occurs in brain areas
associating with movements and sensory crossmodal integration and occurs presumably due
to facial muscle activity. Angry faces elicited left
lateralized activation in brain areas involving in
speech production, which may be considered in
the context of an evolutionary background.
Figure 1: Brain activation in a) observation and imitation conditions, b) imitation versus observation conditions and c) angry
versus happy faces conditions.
84
IZKF Aachen Progress Report 2011
Project Funding
|
Clinical Neurosciences
|
N2-4
2.3.
Funding period: 01.07.2008 - 30.06.2011
Staff: TV-L 13 (Markov V.)
SHK (Semmler F., Mathies L.)
Materials 2011: € 2,300
Investments/Equipment 2011: –
Publications
IZKF relevant, project associated
1. Mathiak, K., Ackermann, H., Rapp, A.,
Mathiak. K.A., Shergill, S., Riecker, A., Kircher,
T.T.J. (2011). Neuromagnetic oscillations and
hemodynamic correlates of P50 suppression
in schizophrenia. Psychiatry Research: Neuroimaging, 194, 95-104. [IF 3.435]
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Mathiak, K.
Thönneßen,
H.
Early processing of emotional
prosody in depression and
serotonergic modulation of
mismatch negativity
DFG MA2631/4-1 03/10-03/13
€ 273,600
Promoting of young researcher
Doctoral Theses
Thönneßen, H.
2011
RWTH Aachen,
Dept. of
Psychiatry,
Psychotherapy
and Psychosomatics
Pre-attentive processing of prosody in
schizophrenia
IZKF Aachen Progress Report 2011
85
2.3.
Project Funding
|
Clinical Neurosciences
|
N2-5
The processing of verbal and nonverbal cues in arithmetic
word problems
Willmes K. (Department of Neurology, Section Neuropsychology)
Based on behavioural results obtained in 2010,
demonstrating facilitating effects of verbal cues
when solving arithmetic word problems, we analyzed fMRI data of 19 healthy male participants
using the same experimental paradigm. As expected, word problems with final questions, which
already proved to be more difficult in the behavioural study, elicited more extensive activations
than parallel problems starting with the question,
with a whole network of frontal, parietal, and
temporal areas (see Figure 1a) showing more
activation. In contrast, we found no additional activation caused by problems with initial questions.
Furthermore, bracketing the second and the
third numerical information caused significantly
more activation in parietal and frontal areas than
grouping the first and the second number (see
Figure 1b). In region of interest (ROI) analyses,
we found stronger and delayed signal changes
in left precuneus for summing up the second and
Figure 1: Activation patterns for a) word problems with initial vs. final questions, and b) bracketing of 1st and
2nd vs. 2nd and 3rd numerical information. c) Time courses of signal change in left precuneus (left panel) for
bracketing of 1st and 2nd (in yellow) and 2nd and 3rd operand (in orange) during the final question condition
and activation patterns for the latter contrast (right panel).
86
IZKF Aachen Progress Report 2011
Project Funding
|
Clinical Neurosciences
|
N2-5
2.3.
Funding period: 01.07.2008 - 30.06.2011
Staff: ½ TV-L 13
(Rath D., Domahs F., Jung S.)
SHK (Rath C.)
Materials 2011: –
Investments/Equipment 2011: –
the third operand with the question in final position (see Figure 1c).
In two new behavioural experiments, we investigated the impact of gesture (n = 21) and prosody
(n = 22) on solving arithmetic word problems.
Data from both experiments revealed shortest
response latencies for problems with congruent
compared to incongruent and neutral gesture
and prosody, but differences were not significant.
Moreover, problems with congruent gesture were
solved significantly less correctly than with incongruent and neutral gesture. Similar results were
obtained for word problems with prosodic cues,
but the effect of congruent prosody did not reach
significance. FMRI data concerning the influence
of different gestural congruency (n = 16) is still
being analyzed.
Publications
IZKF relevant, project associated
1. Domahs F, Nagels A, Domahs U, Whitney C,
Wiese R & Kircher T (in press). Where the
mass counts: Common cortical activation for
different kinds of non-singularity. Journal of
Cognitive Neuroscience [IF 5.357].
Promoting of young researcher
Diploma/Master Theses
Becker, H.
2011
RWTH Aachen,
Faculty of
Medicine
(Section Clinical
Cognition
Research)
The impact of informational structure on the
processing of arithmetic word problems in patients
with frontal brain damage
Postdoctoral lecture qualification
Domahs, F.
2011
University of
Impairments of verbal fact knowledge
Potsdam,
Faculty of Human
Sciences
IZKF Aachen Progress Report 2011
87
2.3.
Project Funding
|
Clinical Neurosciences
|
N2-6
Cerebral correlates of emotional mimic processing in social
situations functioning as empathy cues
Habel, U. (Department of Psychiatry, Psychotherapy and Psychosomatics)
The goal of the project is to study the behavioural,
physiological and neural correlates of dyadic communications. More specifically, the specific influence of three communication channels, speech
content, facial expression, and prosody on emotion
recognition, affective responses and empathy is
measured in schizophrenic and depressed patients
as well as healthy controls using dynamic stimulus
material. The video clips differ in their relative contribution of emotionality in each channel: Besides
a congruent emotional and a congruent neutral
condition, 4 more conditions served to differentially
identify the influence of neutral verbal, non-verbal,
and para-verbal communication channels.
Figure 1: Activation clusters of emotional prosody (upper), emotional
face (middle), and emotional speech content (lower) in 29 healthy
controls (p<.05)
88
IZKF Aachen Progress Report 2011
After validation of 400 video clips (n=28), 96 video
clips were chosen for a behavioural study incorporating measures of electrodermal activity and
heart rate in schizophrenic (N=20) and depressed
(N=29) patients as well as healthy controls (N=38).
Results showed that emotion recognition, affective
responses and empathy rates were highest in all
groups when emotionality was presented congruently across channels. Depressed patients performed worse in all behavioural measures and displayed highest autonomic arousal. Schizophrenic
patients, in contrast, performed only worse than
healthy controls but displayed lowest autonomic
arousal. In general, schizophrenic patients seem
to rely more on speech content while depressed
patients focus more on facial expressions when
correctly recognizing another person’s emotion.
Three papers resulted from the behavioural study
(one published /one submitted in 2011 and another
one will be submitted shortly).
An fMRI study was further carried out to tackle the
neural underpinnings of described interactions in
schizophrenic (N=20) and depressed (N=24) patients as well as healthy controls (N=29). In healthy
controls, results showed that trimodal emotional
communication activated precuneus and thalamus
reflecting multimodal processing and facilitative
effects for empathy. However, bimodal emotional
communication yielded activation in a network associated with theory-of-mind processes, i.e. medial
PFC, orbitofrontal cortex, temporoparietal junction,
temporal pole. This suggested participants’ effort
to infer the mental states of their counterparts and
was accompanied by a smaller reduction of correct emotion recognition rates than the decline of
empathy ratings. Channel-specific emotional contributions were present in modality-specific areas,
i.e. fusiform gyri for facial expressions, Heschl’s
gyri for prosody, and middle temporal gyrus for
speech content (Fig.1). The patient data are currently analyzed and will be submitted in the following months.
Project Funding
|
Clinical Neurosciences
|
N2-6
2.3.
Funding period: 01.07.2008 - 30.06.2011
Staff: ½ TV-L 13 (Schneider D.)
½ SHK (Albers J., Schirk C.)
Materials 2011: € 800
Investments/Equipment 2011: –
Publications
IZKF relevant, project associated
1. Regenbogen, C., Schneider, D., Finkelmeyer,
A., Kohn, N., Kellermann, T., Habel, U. (2011).
The differential contribution of facial expression, prosody, and speech content to empathy.
Cognition & Emotion, 13, 1-20.
2. Schneider, D., Regenbogen, C., Finkelmeyer, A., Kohn, N., Kellermann, T., Habel, U.
Empathic and behavioural responses to dynamic stimuli in depression. Submitted.
3. Regenbogen, C., Schneider, D., Gur, R.E.,
Finkelmeyer, Schneider, F., Habel, U., Kellermann, T. Multimodal human communication
– targeting facial expressions, speech content
and prosody. Submitted.
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Habel, WeishoffHouben, Herwig,
Wolf (GenderAG), Frauen
helfen Frauen
e.V., Kohn,
Schneider
Gender specific assessment and
patient-care following violence
experience in patients in the city
of Aachen
Ministerium für
2011-2014
Gesundheit,
Emanzipation,
Pflege und Alter
(MGEPA) des
Landes NordrheinWestfalen
€ 1,289,800
Habel, Derntl
Neural correlates of cognitiveemotional indicators of gender
stereotype processing in transsexual individuals
DFG (HA 3202/31)
2010-2012
€ 90,000
Jäger, Jarke,
Schneider,
Habel, Willmes,
Koch, Huber
Natural Media and Engineering:
Emotion-Cognition Interactions
and their Modification
RWTH Project
House “Human
Technology”
(HumTec)-Exzellenz Initiative des
Bundes und der
Länder
DFG
10/200809/2011
€ 300,000
Promoting of young researcher
Doctoral Theses
Schneider, D.
Ongoing
University
Empathic behavioural and physiological responses
Hospital Aachen, to dynamic stimuli in depression
Department of
Psychiatry, Psychotherapy and
Psychosomatics
Regenbogen, C.
Ongoing
University
Multimodal human communication – targeting facial
Hospital Aachen, expressions, speech content and prosody
Department of
Psychiatry, Psychotherapy and
Psychosomatics
IZKF Aachen Progress Report 2011
89
2.3.
Project Funding
|
Clinical Neurosciences
|
N3
How the world is represented in the brain? Neural correlates
of multimodal semantic priming in healthy control subjects
and patients with panic disorder
Gauggel S. (Medical Sociology and Medical Psychology)
Huber W. (Department of Neurology)
Emotional information influences our everyday
life in several ways. With the project, we examined the impact of different emotional information on neural correlates of semantic priming in
(a) healthy subjects and (b) patients with major
depression as they suffer from emotional and
cognitive deficits, among others in semantic
processing. Whether these semantic deficits are
cognitive or interact with emotional dysfunctions,
is still an open question.
Stimuli were presented with a short SOA of 200
ms as subjects performed a lexical decision task
during fMRI measurement. The experimental
conditions were: positive, negative, neutral and
panic prime-target pairs. The latter were included
as patients with depression sometimes also show
anxiety related symptoms that might influence the
self-reported severity of illness and might therefore have an influence on cognitive performance.
Nineteen in-patients and nineteen demographically matched controls were recruited.
Behavioral data revealed a priming effect for
positive and neutral information for both groups.
The negative valence induced no effect (controls)
or even inhibition (slower RT for related stimuli) in
patients. The same was true for the panic condition.
On a neural level, the direct comparison between groups revealed
similar neural activation in right
middle frontal regions for patients
and controls. Group differences
emerged in the right fusiform gyrus and the ACC. Activity associated with positive valence differed
at the DLPFC and amygdala and
for negative valence at putamen
and cerebellum. The activation of
amygdala and DLPFC correlated
negatively with the severity of depression. The neural correlates
for the panic condition are still
analyzed.
Overall, the results showed that
emotional information has an influence on semantic association
processes. While positive and
neutral information seem to share
a semantic network, negative relations might induce compensatory mechanisms that inhibit the
Figure 1: (A) Example of the semantic priming task. (B) Examples of neural correlates.
spread of activation between re-
90
IZKF Aachen Progress Report 2011
Project Funding
|
Clinical Neurosciences
|
N3
2.3.
Funding period: 01.07.2008 - 30.06.2011
Staff: TV-L 13 (Saß K.)
½ TV-L 13 (Schneider D., Wojnar A.)
Materials 2011: € 983
Investments/Equipment 2011: –
lated concepts in healthy subjects. In depression,
semantic processing deficits are modulated by
emotional valence of the stimulus on the behavioral as well as on neural level in right-lateralized
prefrontal areas and the amygdala. The results
highlighted an influence of depression severity
on emotion information processing as the severity of symptoms correlated negatively with neural
responses to positively and negatively valenced
information. Hence, the dysfunctional emotion
processing may further enhance the cognitive
deficits in depression.
Publications
IZKF relevant, project associated
1. Sass K., Habel U., Huber W., Sachs O., Gauggel S., Kircher T. (in press). The influence of
emotional associations on the neural correlates of semantic priming. Human Brain Mapping, doi: 10.1002/hbm.21241 [IF: 5.107]
2. Straube B., Green A., Sass K., Kirner A., Kircher T. (in press). Neural integration of speech
and gesture in schizophrenia: Evidence for
dysfunctional processing of metaphoric gestures. Human Brain Mapping [IF: 5.107]
3. Sachs O., Weis S., Zellagui N., Sass K., Huber W., Zvyagintsev M., Mathiak K., Kircher T.
(2011). How different types of conceptual relations modulate brain activation during semantic priming. Journal of Cognitive Neuroscience,
70(4), 1263-1273. [IF: 5.357]
Promoting of young researcher
Diploma Theses
Oetken, S.
2011
RWTH Aachen,
Shared intentions and gestures:
Department
the neurodevelopmental effects in mentalizing
of Psychiatry,
network
Psychotherapy and
Psychosomatics
Kintzel, F.
2011
RWTH Aachen,
The influence of semantic categories on single
Department
word production in schizophrenia and healthy
of Psychiatry,
controls
Psychotherapy and
Psychosomatics
Fetz, K.
2011
RWTH Aachen,
Emotional verbal fluency in psychiatric patients
Department
and healthy controls
of Psychiatry,
Psychotherapy and
Psychosomatics
Doctoral Theses
Mühlhaus, J.
Ongoing
RWTH Aachen,
Neural correlates of the impact of semantic
Department
associations on sentence production
of Psychiatry,
Psychotherapy and
Psychosomatics
Awards
DGPPN Research Award – Imaging in Psychiatry and Psychotherapy
IZKF Aachen Progress Report 2011
91
2.3.
Project Funding
|
Clinical Neurosciences
|
N4
Funding period: 01.07.2011 - 30.06.2014
Materials 2011: € 14,900
Investments/Equipment 2011: –
Impulsivity and Aggression
Habel U. (Department of Psychiatry, Psychotherapy, and Psychosomatics)
The joint venture of projects regarding the topic
“Impulsivity and Aggression”, which started July
1st, 2011, aims at a further clarification of the neuronal and genetic mechanisms underlying aggressive and impulsive behaviour in selected patient
groups and healthy controls. Within this alliance
the first six months were used for the development
and implementation of a new common paradigm
that will be used in each of the individual projects.
This new paradigm, the “modified Taylor Aggression Paradigm” (mTAP), has been developed and
a pilot study on 20 healthy controls has been conducted within two individual projects to ensure
the validity of this new paradigm. Furthermore, a
shared database was implemented and specified
to allow a common access to recruitment sheets,
participant data and encryption methodology.
These processes have been standardized for
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IZKF Aachen Progress Report 2011
all projects as much as possible. Regarding the
joint approach to clarify the genetic mechanisms
of the different aspects of impulsivity and aggression within the individual samples, a database for
genotyping the blood samples taken in every individual projects was established. The procedures
of taking blood samples, labelling and further
analyses were determined and coordinated with
the Institute of Human Genetics. Monthly meetings were implemented and conducted to ensure
coordination of the individual projects and to allow for continuous presentation and evaluation of
progress within the different projects.
To date all associated projects were able to adhere to their time schedules and therefore the
joint venture completed the first six months successfully.
Project Funding
|
Clinical Neurosciences
|
N4-1
2.3.
Funding
Funding period:
period: 01.07.2008-30.06.2011
01.07.2011 - 30.06.2014
Staff: TV-L 13 (Saß K.)
Staff: TV-L
1313
(Pütz
V., Großheinrich
N.)A.)
½ TV-L
(Schneider
D., Wojnar
Materials
Materials 2011:
2011: €
€ 1,200
983
Investments/Equipment
Investments/Equipment 2011:
2011: –
–
Neurobiological and neurocognitive indicators of aggressive
behaviour in preschoolers
Konrad K. (Department of Child and Adolescent Psychiatry and Psychotherapy)
Vloet T. (Department of Child and Adolescent Psychiatry and Psychotherapy)
In recent years, an increase in violent crimes by
children and adolescents can be observed and
many children show high levels of impulsive-aggressive behaviours. Some of these children have
a development towards adult offenders, while
others suffer from a disorder of affective dysregulation. For this reason, DSM-V recommends the
implementation of a new diagnostic category, the
so-called temper dysregulation disorder with dysphoria (TDD). However, until now our knowledge
about aetiology, treatment options and prognosis
of those children is still very limited. Thus the objective of the recent study is to characterize children who demonstrate dysphoric-aggressive behavior as early as possible. We will apply a broad
test battery on emotional and impulse regulation
in order to investigate the basic neurobiological
mechanisms of aggressive behaviour in early
childhood (T1). The behavioural data will be completed by physiological (headless eye tracking,
electrodermal activity, heart rate variability) and
genetic (MAO-A low vs. MAO-A high) measure-
ments. Based on a current model we assume a
distinction between indicators of cognitive-impulsive and disorganized behaviour and indicators
of affective dysregulation. In a longitudinal design
we will examine the predictive value of these variables (T2) using functional magnetic resonance
imaging technique (fMRI).
In 2011, we reconsidered the study design in
close cooperation with the ethical review committee. As a result we dropped the fear conditioning
paradigm. Instead we decided to measure gaze
direction via eye tracking by presenting emotional
(including fearful) faces. We composed the broad
testing battery for T1 and refined the battery to the
specific demands for children (e.g. we prepared
emotional stimuli suitable for small children). In
addition, we designed and programmed the Point
Subtraction Aggression Paradigm (PSAP) for
fMRI and after thorough consideration of all aspects we modified the task for the special use of
preschoolers.
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Schneider
(Sprecher)
International Research
Training Group 1328: Brainbehavior relationship of emotion
and social cognition in schizophrenia and autism
DFG
2010-2014
(Antragsteller:
Amunts, Eickhoff,
Feldmeyer, Gründer,
Habel, HerpertzDahlmann, Kobbelt,
Konrad, Lübke,
Mathiak, Shah,
Willmes)
IRTG 1328
€ 2,1 M
Konrad
Bilateral collaboration
DFG
2010-2011
€ 22,100
Konrad
Long-term Safety of MPH
EU
2010-2015
€ 320,000
IZKF Aachen Progress Report 2011
93
2.3.
Project Funding
|
Clinical Neurosciences
|
N4-1
HerpertzDahlmann &
Konrad
Behavioural, developmental and
neural effects of a standardized
mother-child intervention
programme in adolescent
mothers and their children
BMBF
2012-2015
HerpertzDahlmann &
Konrad
Neuropsycholocial functioning
and structural and functional
brain abnormalities in Anorexia
nervosa before and after
treatment
BMBF
2007-2012
€ 256,440
Promoting of young researcher
Diploma Theses
Jamnicki, A.
Ongoing
University of
Maastricht
Impact of aggressive behaviour in boys on inhibition in an emotional GoNogo task
Postdoctoral lecture qualification
Vloet, T.
94
Ongoing
RWTH Aachen,
Faculty of
Medicine
Neurobiological aspects of antisocial disorders
Gr ossheinrich, N. Ongoing
RWTH Aachen,
Faculty of
Medicine
Development of affective dysregulation in children
and adolescents at risk
IZKF Aachen Progress Report 2011
Project Funding
|
Clinical Neurosciences
|
N4-2
2.3.
Funding period: 01.07.2011 - 30.06.2014
Staff: TV-L 13 (Klasen M.)
SHK (Ryszka D.)
Materials 2011: € 9,800
Investments/Equipment 2011: –
Genetic-pharmacological imaging of the serotonergic system
in violent video games
Mathiak K. (Department of Psychiatry and Psychotherapy)
Zepf F. (Department of Child and Adolescent Psychiatry and Psychotherapy)
Aggressive behavior (AB) is a major burden to society with severe socio-economic consequences.
Genetic studies suggest a genetic contribution to
AB; in particular, the low expressing allele of the
MAOA gene (MAOA-L) has been associated with
increased AB. Recent neural aggression models
have suggested a dysfunctional emotion regulation circuit including amygdala, orbitofrontal, and
anterior cingulate cortex (ACC). Dysregulated serotonergic (5-HT) projections from the ACC to the
amygdala have been suggested to promote aggressive behavior. However, due to methodological and ethical constraints, the neural substrates
of AB are difficult to assess. A possible solution
is the use of virtual violence which permits AB
against virtual characters without direct consequences for any real person and can be easily
applied in functional imaging experiments. AB in
violent video games affects rostral anterior cingulate cortex (ACC) and amygdala, in line with the
suggested neurophysiological circuits underlying
real-life AB. Preliminary results from a study with
the 5-HT 1A agonist quetiapine suggest a modification of the AB specific patterns by a functional
modulation of the serotonergic system (Figure 1).
We developed a novel experimental paradigm for
the assessment of brain activation patterns during virtual AB in a violent video game with functional magnetic resonance imaging under three
experimental conditions in randomized, doubleblind fashion: 1) Increase of synaptic 5-HT with a
selective serotonin reuptake inhibitor (SSRI, Cipralex ®); 2) reduction of synaptic 5-HT with the
Rapid Tryptophan Depletion Test (RTD); and 3)
Placebo. A blood sample genotyping will assess
the allelic expression of the MAOA gene. Furthermore, we developed an fMRI compatible adaptation of the Taylor Competitive Reaction Time
Task, which will serve as an additional paradigm
for the assessment of event-related fMRI during
aggressive actions.
Figure 1: Modification of ACC-amygdala connectivity by a serotonergic drug
IZKF Aachen Progress Report 2011
95
2.3.
Project Funding
|
Clinical Neurosciences
|
N4-3
Funding period: 01.07.2011 - 30.06.2014
Staff: TV-L 13 65% (Brünner Y.)
Materials 2011: € 3,000
Investments/Equipment 2011: –
Aggression in the context of situational stimuli
Wiesmann M. (Department of Diagnostic and Interventional Neuroradiology)
The project goals for the first half year were the
establishment of chemosensory expertise in
combination with functional imaging studies as
well as the development of behavioral and imaging paradigms.
During the last six month Jessica Freiherr established a junior research group consisting of two
PhD students and five MD students. This group
is engaged with neuroscientific research about
chemosensory perception. The protocol for the
study at hand was reviewed and is already approved by the ethics committee of the University
Hospital Aachen.
During the first months, the PhD student working on this project, Lies Gysemans MSc Psych,
acquired knowledge about the chemical senses
by intensive review of the existing literature and
training regarding different olfactory testing techniques. Additionally, Gysemans participated in
different courses “Smell and Taste 03 – a practical introduction to the physiology and pathophysiology of the chemical senses”, “MRI basics”, “AD
Instruments PowerLab & LabChart”and “SPM
8”. She was also trained to run the MRI scanner
as well as to conduct a body odor donation and
application of chemosensory stimuli. A first pilot
study involving donation and application of body
odor stimuli will be conducted in February 2012.
In December Lies Gysemans applied for a research grant with the topic “Human chemosensory communication of social information” to the
DAAD.
Within the research network several tools that
can be used by researchers within the different
projects were developed. All principal investigators use one subject database as well as a common behavioral paradigm to induce aggression
in the MRI scanner. A first pilot study to optimize
the behavioral paradigm PSAP (Point Substraction Aggression Paradigm) was conducted in 20
healthy subjects. The results of this pilot study
are currently analyzed.
The project goals for the first six months of the
project were achieved. Modifications of the project with regards to the original proposal are to
date not foreseeable.
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Gysemans, L. Human chemosensory communica- DAAD
tion of social information
applied
Promoting of young researcher
Doctoral Theses
Gysemans, L.
96
IZKF Aachen Progress Report 2011
Ongoing
RWTH, Faculty
of Medicine,
Neuroradiology
Impact of chemosensory signals during communication of aggression in humans
Project Funding
|
Clinical Neurosciences
|
N4-4
2.3.
Funding period: 01.07.2011 - 30.06.2014
Staff: TV-L 13 (65%): Voss, B. (50%),
Mühlhaus, J. (15%)
SHK Nowag, S.
Materials 2011: € 900
Investments/Equipment 2011: –
Impulsivity and aggression in borderline personality disorder
and Huntington’s disease
Habel U. (Department of Psychiatry and Psychotherapy)
Reetz K. (The Institute for Medical Neuroscience and Medicine Jülich)
The present project regards the characteristic of
aggression and impulsivity in patients fulfilling the
diagnostic criteria of a borderline personality disorder and patients with Huntington’s disease. The
objective is to specify aggressive and impulsive
behaviour of these patients by means of behavioural assessment and neuroimaging methods.
Starting July 1st 2011, the scheduled timetable
could be maintained. So far, the ethical vote for
the project was obtained and the details of the
assessments were configured. Within the joint
venture of the associated projects, a common
paradigm examining specific aspects of aggressive behaviour, the “Modified Taylor Aggression
Paradigm (mTAP)”, was developed and within the
present project, a pilot study on healthy subjects
was conducted to ensure the validity of this paradigm. Subsequent to this pilot study, recruitment
of patients within hospital wards has started and
contact with external support groups have been
established.
Furthermore, recruitment and screening of controls also started, the first blood samples are
taken and the first assessments have been completed. FMRI measurement for these control participants still has to be done.
Implementation of fMRI-paradigms is virtually
completed and corresponding pilot testing has
been done. In addition, a talk regarding the project and the underlying research question was
given at a conference in Goettingen, September
2011 (“Empirische Forschung in der forensischen
Psychiatrie, Psychologie und Psychotherapie”,
15.-16.9.2011, Goettingen), followed by the preparation of a corresponding book chapter which
will be published in 2012 (“Empirische Forschung
in der Forensischen Psychiatrie”, Editor: J. Mueller, MWV-Berlin).
To conclude, all preparations have been completed, so the time schedule can be adhered to.
Promoting of young researcher
Doctoral Theses
Bischoff, B.
Ongoing
RWTH Aachen,
Department of
Psychiatry,
Psychotherapy,
and Psychosomatics
Impulsivity and MAO-A genotype
IZKF Aachen Progress Report 2011
97
2.3.
Project Funding
|
Clinical Neurosciences
|
N4-5
Staff: TV-L 13 (65%) (Schlüter T.)
Materials 2011: € 6,750
Investments/Equipment 2011: –
Context-Sensitive Influence of MAOA-Genotype on Dopaminergic Mechanisms of Antisocial Behavior and Aggression
Mottaghy F. ( Department of Nuclear Medicine)
Vernaleken I. (Department of Psychiatry, Psychotherapy, and Psychosomatics)
The main project goals for 2011 have been the
establishment and validation of experimental
methods and the application for the vote of the
Ethics Committee of RWTH Aachen. Furthermore, the applications for the Bundesamt für
Strahlenschutz (BfS) andparticipant/patient insurance needed to be completed.
Based on a manual by Cherek (1992), a modified version of the Point Subtraction Aggression
Figure 1: Linear Relationship between aggressive responding on the
PSAP and Reward Dependence.
Paradigm (PSAP), adapted to the particular demands of the present study, was programmed on
presentation. The validity of this paradigm was
confirmed by correlations between aggressive
responding on the PSAP and relevant personality factors (see figure 1). Furthermore, a reliable
method for the tracer synthesis according to good
manufacturing practice (GMP) was established in
collaboration with the University of Mainz.
For the Ethics Committee-application a study
protocol and patient/participant information were
written and adapted in respect to the issues that
were stated by the Ethics Committee. On December 6th, a positive ethic vote was given by the
committee. Based on the positive ethical vote of
the Ethics Committee the application for the participant/patient insurance was submitted on December 20th, 2011. We expect the respective quotation by the end of January 2012. On December
23th, 2011 the application forms concerning the
BfS vote were submitted. We expect a decision
by April/May 2012.
In January 2012 the recruitment phase was started. Study flyers have been distributed throughout
Aachen. Additionally, an online post was placed
on the website “campuslive.de.”
Promoting of young researcher
Diploma Theses
Schlüter, T.
98
IZKF Aachen Progress Report 2011
2011
Maastricht
University,
Faculty of
Psychology and
Neuroscience
RWTH, Faculty
of Medicine
The Impact of Dopamine on Aggression:
An [18F]DOPA PET Study
Project Funding
|
Clinical Neurosciences
|
N5
2.3.
IZKF Aachen Progress Report 2011
99
Funding period: 01.07.2011 - 30.06.2014
Materials 2011: € 23,775
Investments/Equipment 2011: € 1,050
Molecular and cellular mechanisms of degenerative
axonopathies
Weis J. (Department of Neuropathology)
Several factors contribute to the exceptional
vulnerability of neurons to insults compared to
other cells, including the long life span and the
extremely elongated axonal processes of most
nerve cells. Neurons require efficient transport
processes for intracellular communication and
redistribution of cargo and need to deal with toxic
products including misfolded proteins that might
accumulate. This joint project is designed to elucidate pathomechanisms of degenerative axonopathy in frequent, paradigmatic neurodegenerative
diseases of similar pathophysiology, Parkinson’s
disease (PD), amyotrophic lateral sclerosis (ALS)
and Charcot-Marie-Tooth neuropathies (CMT).
Particular emphasis is put on protein aggregates that form in these diseases and interfere
with transport processes,
thereby disturbing vital
communication
along
axons. Moreover, the disposal of these aggregates
by autophagy will be an
additional focus. Finally
we will initiate searches
for novel genes and their
products involved in neurodegenerative diseases.
Our joint project will integrate biochemical, cell
biological,
histological
and genetic approaches.
This effort is expected to
provide novel insights into
the pathomechanisms of
neurodegenerative diseases. It should thus contribute to the development
of new methods for early
diagnosis and therapy of
these disorders.
This collaborative project is based on the
achievements of the project “Cellular and molecular pathogenesis of motor neuron degeneration” of the previous funding period (see N1). It
is expected to improve the prospects of a future
collaborative proposal for funding by the German
Research Council (DFG) on cellular and molecular mechanisms of neurodegenerative diseases.
2.3.
Project Funding
|
Clinical Neurosciences
|
N5-1
Funding period: 01.7.2011 - 30.06.2014
Staff: TV-L 13 (Saridaki T.)
Materials/Travel expenses 2011: € 1,050
Investments/Equipment 2011: € 5,000
Dynein-mediated transport and clearance
of protein aggregates
Falkenburger B. (Department of Neurology)
Schulz J. B. (Department of Neurology)
Several neurodegenerative disorders are characterized and potentially caused by protein aggregates - e.g. Parkinson‘s disease by aggregates
of _-synuclein. We have previously found that
cells sequester _-synuclein aggregates into aggresomes, which can then be cleared from the
cell entirely. Our aim is to identify new potential
therapeutic targets for aggregopathies by studying the molecular components that constitute
this pathway. During the first 6 months of the
project we interviewed postdoc candidates and
hired Dr. T.S. We built our toolkit by amplifying
the sequences of our proteins of interest from a
cDNA library followed by cloning and testing of
EGFP and mCherry tagged versions thereof. In
search for modifiers of _-synuclein aggregates
we identified expected candidates such as p62
and unknown proteins such as LAP3. p62 links
ubiquitinated proteins to the nascent autophagic
membrane; LAP3 is a protein of unknown function identified as a modifier of tau pathology in
our drosophila screen. Finally, we built and tested
the life-cell-microscope which will now allow us to
address modification of aggregate transport and
clearance more directly.
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Schulz, J.B.
NGFNplus (Functional Genomics of BMBF/
Parkinson‘s Disease)
01GS08137
2011-2013
€ 400,000
(own part)
Schulz/Voigt
Competence Network Degenerative BMBF/01GI1005C 2011-2014
Dementias
€ 148,000
(own part)
Schulz, J.B.
European Friedreich Ataxia
Consortium for Translational
Studies
€ 850,000
(own part)
Promoting of young researcher
Postdoctoral lecture qualification
100
Falkenburger, B.
Ongoing
RWTH Aachen
Saridaki, T.
Ongoing
RWTH Aachen
IZKF Aachen Progress Report 2011
EU FP7,
collaborative
project #242193
2010-2014
Project Funding
|
Clinical Neurosciences
|
N5-2
2.3.
Funding period: 01.07.2011 - 30.06.2014
Staff: ½ TV-L 13 (Flick F., Otten D.)
Materials 2011: € 7,500
Investments/Equipment 2011: –
Control of protein aggregation and autophagy by SIRT2
Lüscher B. (Department of Biochemistry and Molecular Biology)
Neurodegenerative processes are associated
with the accumulation of misfolded protein aggregates, which is closely linked to cellular stress.
Inadequate processing of protein aggregates,
e.g. by the autophagosomal system, is critical
for the phenotype because these aggregates
affect normal physiological protein turnover and
intracellular transport processes. Both are regulated by posttranslational modifications including
acetylation. We wanted to address the functional
relevance of the CDK5-SIRT2-HDAC6 regulatory
network for protein aggregation and neurotoxicity. Therfore we finished the evaluation of newly
generated mAbs (in cooperation with Dr. Elisabeth Kremmer, Munich) against SIRT2 C-terminal
peptides phosphorylated at either Ser-331 and/
or Ser-335. We selected mAbs that specifically
recognize all different isoforms of C-terminally
phosphorylated SIRT2 in immunoblot and immunofluorescence experiments. With these reagents we will be in the position to measure the
phosphorylation status of SIRT2 under different
physiological conditions. We already observed
different phosphorylation pattern at Ser-331 of
human SIRT2 in Drosophila models that were dependent on highly conserved CDK5. As there is
a multitude of knockout flies for different kinases
available, we are planning to screen the unknown
Ser-335 targeting kinase in this system (in cooperation with A. Voigt, Institute of Neurology).
Furthermore we identified GCN5 as a lysineacetyltransferase that targets CDK5 in vitro and
in cells as well as SIRT2. GCN5 thus provides
another level of complexity in the CDK5-SIRT2HDAC6 regulatory network.
SIRT2 knockdown led to beneficial effects in cell
culture models of Huntington’s disease. In absence of the deacetylase we observed less accumulation of mutant protein attended by a lower
apoptosis rate. Moreover we could confirm the
influence of SIRT2 on autophagic degradation
measuring p62 turnover. Initial experiments denote the relevance of the two named phorsphorylation sites, which will be analysed in detail.
Publications
IZKF relevant, project associated
1. Flick F, Lüscher B (2012) Regulation of sirtuin function by posttranslational modifications.
Front Pharmacol. 3:29
Promoting of young researcher
Bachelor Theses
Schall, N.
2011
RWTH Aachen, Institute Regulation of the p35/CDK5 kinase complex
of Biochemistry and
and its role in controlling SIRT2 in melanoma
Molecular Biology
Flick, F.
2011
RWTH Aachen, Institute Regulation of the NAD+-dependent
of Biochemistry and
deacetylase SIRT2 by CDK5
Molecular Biology
Otten, D.
Ongoing
RWTH Aachen, Institute Function of SIRT2 in neurodegenerative
of Biochemistry and
disorders
Molecular Biology
Doctoral Theses
IZKF Aachen Progress Report 2011
101
2.3.
Project Funding
|
Clinical Neurosciences
|
N5-3
Degenerative axonopathy of skin nerve fibers in Parkinson’s
disease, Amyotrophic Lateral Sclerosis and in axonal CharcotMarie-Tooth neuropathy
Weis J. (Department of Neuropathology)
Alterations of axonal transport are important determinants of the pathogenesis of neurode-generation. We study pathomechanisms of axonal
changes in related neurodegenerative diseases
with a focus on proteins involved in vesicular trafficking and endoplasmic reticulum function.
Important milestones reached in 2011 include:
• In cooperation with Univ.-Prof. Dr. K. Reetz,
Figure 1: Accumulation of mitochondria, autophagic vacuoles and
other organelles in distal axonopathy due to mutation of the neurofilament light chain in a CMT patient (in cooperation with Dr. M. Elbracht, Dr. J. Senderek, Prof. S. Rudnik-Schöneborn and Univ.-Prof.
K. Zerres, Institute of Human Genetics, RWTH)
Dept. of Neurology, and Dr. V. v. Felbert, Dept.
of Dermatology, skin biopsies from a cohort of
patients with Parkinson’s dis-ease and related
disorders were collected. These biopsies were
analyzed by immu-nohistochemistry and electron microscopy for alterations of skin nerve
fibers.
• Mice lacking the motor neuron disease protein
VAPB were generated and bred in co-operation
with Univ.-Prof. Tolba, Dr. Teubner and Mrs.
Tropartz, Institute of Experi-mental Animal Research, RWTH
• Extending the analysis of distal axonopathy
from skin axons to other important axonal populations, we investigated peripheral nerve fiber
and muscle fiber changes in he-reditary and
sporadic ALS cases with special focus on alterations of the VAPB protein which is involved in
endoplasmic reticulum functions and vesicular
trafficking.
• In cooperation with Prof. M. Auer-Grumbach,
Graz, and Prof. C. Blackstone, NIH, Be-thesda,
MD, USA, we are investigating the role of the
ER protein atlastin-1 in the maintenance of distal axons (Guelly et al., 2011).
Publications
IZKF relevant, project associated
1. Guelly C, Zhu PP, Leonardis L, Papic L, Zidar
J, Schabhüttl M, Strohmaier H, Weis J, Strom
TM, Baets J, Willems J, De Jonghe P, Reilly
MM, Fröhlich E, Hatz M, Trajanoski S, Pieber
TR, Janecke AR, Blackstone C, Auer-Grum-
102
IZKF Aachen Progress Report 2011
bach M. Targeted high-throughput sequencing
identifies mutations in atlastin-1 as a cause of
hereditary sensory neuropathy type I. Am J
Hum Genet. 88(1): 99-105, 2011. [IF 11,7]
Project Funding
|
Clinical Neurosciences
|
N5-3
2.3.
Funding period: 01.07.2011 - 30.06.2014
Staff: TV-Ä 1 (Nolte K.)
Materials 2011: € 5,000
Investments/Equipment 2011: –
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Weis, J.
Auswirkungen der Mutati-on des
Deutsche
VAPB-Proteins in der Pathogenese Gesellschaft für
der ALS8
Muskelkranke
(DGM)
7/20106/2012
€ 30,000
Weis, J.
Krüttgen, A.
Zerres, K.
Pathogenesis of hereditary sensory DFG; WE
and motor neu-ropathies:
1406/13-1
Integrating neu-ropathology and
molecular genetics
2010-2013
€ 400,000
Weis, J.
Kretzschmar
(München),
Thal (Ulm)
The German MND Tissue Bank
3/20122/2015
€ 120,000
BMBF120203
Promoting of young researcher
Diploma Theses
Buchkremer, S.
Ongoing
RWTH Aachen,
Faculty 1
Identification of new factors from the SIL1
interactome
Bauschulte, J.H.
Ongoing
RWTH Aachen,
Effects of lysophosphatic acid on nerve growth
Faculty of Medicine factor and tropomyosin-related kinase A receptor
signal transduction
Meinhardt, A.
Ongoing
RWTH Aachen,
Genotype-phenotype correla-tion in neuropathies
Faculty of Medicine due to MPZ mutation
Katona, I.
Ongoing
RWTH Aachen,
Pathogenesis of HSANs
Faculty of
Medicine and
Faculty 1
(MD-PhD program
Wagner, S.
Ongoing
RWTH Aachen,
ALS: Clinico-neuropathological correlations
Faculty of Medicine
Bushuven, E.
Ongoing
RWTH Aachen,
VAPB in the pathogenesis of ALS
Faculty of Medicine
Nikolin, S.
Ongoing
RWTH Aachen,
Patterns of characteristic mus-cle fiber alterations
Faculty of Medicine in ALS
Doctoral Theses
IZKF Aachen Progress Report 2011
103
2.3.
Project Funding
|
Clinical Neurosciences
|
N5-4
Identification and characterization of novel genes for
hereditary axonopathies
Senderek J. (Institute for Human Genetics and Department of Neuropathology)
Rudnik-Schöneborn S. (Institute for Human Genetics)
The goal of this project is the identification of
genes involved in monogenic forms of axonopathies. Methodologically, we investigate families
segregating axonal types of Charcot-Marie-Tooth
neuropathies (CMT2) and spinal muscular atrophies (SMA) by genome-wide SNP genotyping
and DNA sequencing. In case of positive results,
we will validate and extend our findings in independent cohorts presenting with these conditions.
We will also investigate the etiology of CMT2/
SMA by functional analyses of the identified gene
products, by using cellular and molecular assays,
banked tissue samples, and animal models accessible through the other subprojects.
Genome-wide genotyping in two families with
autosomal dominant and autosomal recessive
CMT2, respectively, and no mutation in any
known CMT2 gene yielded potential novel loci.
Large-scale DNA sequencing of positional candidate genes is ongoing and we are expecting to
get hold of the results in due course.
We have established the molecular diagnosis in
a family with autosomal dominant SMA through
identification of a SETX mutation. Our results
expand the phenotype associated with SETX
mutations supporting the notion that patients with
autosomal dominant SMA should be investigated
for SETX mutations (Rudnik-Schöneborn et al.,
2011).
We have also contributed to the discovery of a
new CMT gene (Auer-Grumbach et al., 2011) and
a methodological paper presenting an effective
approach for a molecular diagnosis in autosomal
recessive CMT (Fischer et al., 2011).
Publications
IZKF relevant, project associated
1. Auer-Grumbach M, Weger M, Fink-Puches
R, Papić L, Fröhlich E, Auer-Grumbach P, El
Shabrawi-Caelen L, Schabhüttl M, Windpassinger C, Senderek J, Budka H, Trajanoski S,
Janecke AR, Haas A, Metze D, Pieber TR,
Guelly C. Fibulin-5 mutations link inherited
neuropathies, age-related macular degeneration and hyperelastic skin (2011) Brain
134:1839-52. [IF: 9.23]
2. Fischer C, Trajanoski S, Papić L, Windpassinger C, Bernert G, Freilinger M, Schabhüttl
M, Arslan-Kirchner M, Javaher-Haghighi P,
104
IZKF Aachen Progress Report 2011
Plecko B, Senderek J, Rauscher C, Löscher
WN, Pieber TR, Janecke AR, Auer-Grumbach
M (2011) SNP array-based whole genome
homozygosity mapping as the first step to a
molecular diagnosis in patients with CharcotMarie-Tooth disease. J Neurol DOI: 10.1007/
s00415-011-6213-8. [IF: 3,85]
3. Rudnik-Schöneborn S, Arning L, Epplen JT,
Zerres K (2011) SETX gene mutation in a family diagnosed autosomal dominant proximal
spinal muscular atrophy. Neuromuscul Disord
DOI: 10.1016/j.nmd.2011.09.006. [IF: 2,76]
Project Funding
|
Clinical Neurosciences
|
N5-4
2.3.
Funding period: 01.07.2011 - 30.06.2014
Staff: TV-L 9 (Diepolder I.)
Materials 2011: € 6,275
Investments/Equipment 2011: –
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Rivolta
Senderek, J.
Chrast
Gene hunting for recessive
peripheral neuropathies by recent
and highly-parallel technologies
Gebert-RüfStiftung, Basel
07/201006/2013
Senderek, J.
Heisenberg-Stipendium
DFG - Se 1839/1- 09/20081
08/2011
€ 255,000
own part: ca.
€ 102,000
€ 160,000
Promoting of young researcher
Appointments to other universities
Senderek, J.
Ludwig-Maximilians-University, Munich
W2
accepted
IZKF Aachen Progress Report 2011
105
2.3.
Project Funding
|
Clinical Neurosciences
|
N6
Funding period: 01.07.2011 - 31.12.2012
Staff: 65% TV-L 13 (Bresenitz P.)
Materials 2011: € 2,000
Investments/Equipment 2011: –
Acid-sensing ion channels (ASICs) and the pathophysiology
of hepatic encephalopathy
Gründer S. (Institute of Physiology)
To elucidate the potential role of acid-sensingion-channels (ASICs) during hepatic encephalopathy, we first investigated the acute modulation
of ASICs by pathophysiological concentrations of
ammonium in cultured cortical neurons of mice.
We found that 2-4 mM ammonium decreased pH
6.6 induced ASIC-currents in a dose-dependent
manner when ammonium was pre-applied but
not when it was co-applied. Currently, we try to
identify the subunit composition of the channel
responsible for the modulation in a heterologous
expression system (CHO cells).
In addition, we investigated the chronic modulation of ASICs by ammonium. To this end, we cul-
tured cortical neurons for 10 days with 0.1 or 1.0
mM ammonium and determined the abundance
of the main ASIC subunits in the CNS (ASIC1a,
2a, and 2b) by performing quantitative Real-Time
PCR. Preliminary results showed no alteration
in the expression level of ASIC mRNAs. Moreover, electrophysiological recordings showed no
change in the density of ASIC currents after 10
days incubation with ammonium.
Taken together, so far our results uncovered an
acute modulation of cortical ASICs by ammonium, whereas definite conclusions about chronic
effects need further investigation.
Figure 1: Acute effects of ammonium on cortical ASIC currents.
A) Representative current trace
of a whole-cell recording from
a cortical neuron illustrating decreased amplitude of the ASIC
current after pre- and co-incubation with ammonium. B) Quantification of ammonium-induced
modulation of ASIC currents in
cortical neurons.
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Gründer, S.
Molecular and functional
characterization of peptide-gated
ion channels from the freshwater
polyp Hydra magnipapill
DFG GR 1771/7-1 2010 - 2013
~ € 285,000
Promoting of young researcher
Doctoral Theses
Bresenitz, P.
106
IZKF Aachen Progress Report 2011
Ongoing
RWTH Aachen,
Faculty 1
Modulation of Acid-Sensing Ion Channels by NH4+
2.3.
IZKF Aachen Progress Report 2011
107
PROJECT FUNDING
Inflammation and Consequences
In 2011, the IZKF funded 13 projects with € 518,412 in the research
focus area Inflammation and Consequences.
2.4.
Project Funding
|
Inflammation and Consequences
PROJECT FUNDING
Inflammation and Consequences
FINAL REPORTS
E1 | JOINT RESEARCH PROJECT Tacke | 01.07.2008 - 30.06.2011
Acute tissue injury
p. 112
E1-1 | Lüdde | 01.07.2008 - 30.06.2011
Molecular mechanisms of hepatic ischemia/reperfusions injury
p. 113
E1-2 | Ostendorf | 01.07.2008 - 30.06.2011
Mechanisms of inflammatory podocyte damage
p. 115
E1-3 | Uhlig| 01.07.2008 - 31.08.2011
Pathomechanisms in late phase of acute lung injury
p. 116
E1-4 | Wasmuth | 01.07.2008 - 30.06.2011
Importance of the chemokine scavenger receptor D6 for acute liver injury
p. 117
E2 | Tenbrock | 01.07.2008 - 30.06.2011
Relevance of CREM a in the T-cell pathophysiology of SLE
p. 118
E3 | Möller | 01.07.2008 - 30.06.2011
Acute glomerular injury of the kidney
p. 120
E 4 | Streetz | 01.07.2008 - 31.12.2011
Characterisation of mechanisms of HGF/c-Met dependent cytoprotection in
hepatocytes during the liver development and in a model of experimental hepatitis
p. 122
E5 | Wasmuth | 01.07.2008 - 30.06.2011
Functional importance of the chemokin RANTES and its receptors for fatty liver
disease and obesity
p. 124
PROGRESS REPORTS
E6 | JOINT RESEARCH PROJECT Huber | 01.07.2011 - 30.06.2014
Stress signals in aseptic inflammation
110
IZKF Aachen Progress Report 2011
p. 126
Project Funding
|
Inflammation and Consequences
2.4.
p. 129
E6-1 | Vervoorts/Lüscher | 01.07.2011 - 30.06.2014
Investigation of the LPS/TLR4-induced autophagy pathway downstream of p38:
Connection to cell cycle regulators
E6-2 | Huber | 01.07.2011 - 30.06.2014
Reprogramming of the allergic mast cell response by low-dose endotoxin
p. 131
E6-3 | Müller-Newen | 01.07.2011 - 30.06.2014
Anti-inflammatory activity of persistently activated STAT3
p. 133
E6-4 | Ostareck-Lederer/Ostareck | 01.07.2011 - 30.06.2014
Characterization of miRNAs as modulators of TLR4-mediated MAPK signaling
p. 135
E6-5 | Trautwein | 01.07.2011 - 30.06.2014
Relevance of death receptors for NEMO-dependent hepatitis
p. 137
E6-6 | Uhlig | 01.07.2011 - 30.06.2014
The role of neuropeptide Y and the sympathetic nervous system in the
regulation of ventilator-induced lung injury
p. 138
E6-7 | Tenbrock | 01.07.2011 - 30.06.2014
Relevance of CREM_ for the T cell pathophysiologie in SLE
p. 139
p. 141
E6-8 | Tacke/Martin | 01.07.2011 - 30.06.2014
Analysis of molecular mechanisms of cellular communication during initiation
of inflammatory responses following acute liver injury by two-photon microscopy
E6-9 | Ludwig | 01.07.2011 - 30.06.2014
Role of the metalloproteinase ADAM10 in acute and chronic inflammatory
processes in the lung
p. 143
E6-10 | Ostendorf/Floege | 01.07.2011 - 30.06.2014
Platelet-derived growth factors in acute kidney injury
p. 145
E6-11 | Weiskirchen/Borkham-Kamphorst | 01.07.2011 - 30.06.2014
Lipocalin 2 (LCN2), a central mediator in inflammatory organ disease
p. 146
IZKF Aachen Progress Report 2011
111
2.4.
Project Funding
|
Inflammation and Consequences
|
E1
Funding period: 01.07.2008 - 30.06.2011
Materials 2011: € 56,000
Investments/Equipment 2011: –
Acute tissue injury
Tacke F. (Department of Medicine III)
Möller M. (Department of Medicine II)
Acute organ injury, typically caused by inflammatory, ischemic, toxic or metabolic mechanisms,
represents a major problem to medicine and
health care, because it is associated with considerable acute mortality and oftentimes leads
to chronic organ failure. The joint interdisciplinary research consortium E1 has studied principal
mechanisms and consequences of acute organ
injury, using innovative and sophisticated experimental in vivo approaches. The major organs
studied within this consortium were the lung (13), liver (1-1, 1-4) and kidney (1-2, E3).
As depicted in the figure, the main goals of the
consortium were the development of novel invivo-models for organ injury including transgenic mice, the identification of general and or-
Figure 1: Structure of the joint research consortium on acute organ injury
112
IZKF Aachen Progress Report 2011
gan-specific intrinsic pathways of injury, as well
as the delineation of important mechanisms of
the inflammatory reaction towards injury involving cell-intrinsic and immune-mediated aspects
again. During the past funding period, all projects
established a close collaboration and shared
many methods and ideas, resulting in important
scientific advances, but also in the new inflammation-research consortium for the following funding period within the IZKF (which included also
several additional project leaders) as well as in
a proposal for a new SFB (Exploratory Research
Space), which is currently being prepared. Detailed results and achievements (publications,
third party funding, diploma and PhD thesis completions) are described by the individual projects.
Project Funding
|
Inflammation and Consequences
|
E1-1
2.4.
Funding period: 01.07.2008 - 30.06.2011
Staff: ½ TV-L 13 (Janssen J.)
Materials 2011: € 9,950
Investments/Equipment 2011: –
Molecular mechanisms of hepatic ischemia/reperfusions
injury
Lüdde T. (Department of Medicine III)
Trautwein C. (Department of Medicine III)
The aim of this project was to determine molecular mechanisms of ischemia/reperfusion injury.
We could show that the damage occurring in
the liver upon ischemic stress is mainly caused
by programmed necrosis and not apoptosis. A
mouse model represents a knockout of TAK1 in
the liver which shows spontaneous necrosis ultimately causing biliary ductopenia. The necrotic
hepatocytes in this model are morphologically
very similar to the necrotic damage seen upon
ischemia/reperfusion. IF NEMO is additionally
knocked out in the TAK1 deficient livers, these
necrotic areas and thus, the ductopenia, disappear, showing that the necrotic phenotype of the
TAK1 deficient livers is mediated by an NF- B independent function of NEMO.
During the last part of the funding period (2011)
we sought to further elaborate the function of
NEMO in this process. Therefore, we applied our
model of experimental hepatic ischemia/reperfusion injury. Mice with a knock out of Caspase8
in the liver showed a massive increase of liver
damage upon I/R, with large necrotic areas in the
affected liver lobes. Again, this damage was significantly decreased by an additional knock out of
NEMO in these livers. The double knock out of
Caspase8 and NEMO in the liver showed damage similar to that seen in wildtype mice. In order
to further dissect molecular targets of NEMO, we
established a model of in vitro Hypoxia/Reoxygenation (Fig.1 in vitro Hypoxia model). By using
this model, we can specifically explore the role
of signalling molecules in hepatocytes without
the influence of infiltrating immune cells as in the
hepatic I/R model. With these tools, we hope to
unravel the complex mechanisms of NEMO-dependent programmed necrosis.
Figure 1: Establishment of an in vitro hypoxia/reoxygenation model for the further
IZKF Aachen Progress Report 2011
113
2.4.
Project Funding
|
Inflammation and Consequences
|
E1-1
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Lüdde, T.
The role of inflammatory signaling ERC Starting
pathways in acute and chronic liver grant 208237
diesease and liver cancer
09/200808/2013
granted
€ 1,600,356
Lüdde, T.
The function of TAK1 in liver cancer Deutsche
Krebshilfe
accepted in
appr.
Dez.2011,
€ 400,000
written approval
pending
Promoting of young researcher
Doctoral Theses
Janssen, J.
Ongoing
RWTH Aachen, Molecular mechanisms of hepatic Ischemia/
Faculty of
Reperfusion injury
Mathematics,
Computer
Science and
Natural Sciences
Bettermann, K.
2011
RWTH Aachen, The role of TAK1 in liver cancer
Faculty of
Mathematics,
Computer
Science and
Natural Sciences
Awards
2011 Thannhauser-Award of the Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten
(DGVS)
2011 Member of the EMBO Young Investigator Programme
114
IZKF Aachen Progress Report 2011
Project Funding
|
Inflammation and Consequences
|
E1-2
2.4.
Funding period: 01.07.2008 - 30.06.2011
Staff: ½ TV-L 10 (Bataille N.)
Materials 2011: € 14,150
Investments/Equipment 2011: –
Mechanisms of inflammatory podocyte damage
Ostendorf T. (Internal Medicine II)
Floege J. (Internal Medicine II)
Most renal diseases start in the glomerulus, where
podocytes represent the glomerular “Achilles
heel” since they have only a very limited capacity to adapt to renal damage. Both, the attempt
of cell division (with loss of cells into urine) and
necrosis/apoptosis participate in podocytopenia,
which is assumed to be the main cause of glomerulosclerosis. By podocyte specific deletion of
either Caspase 8 or NEMO (IKK-a) we here follow
the hypothesis that podocytic Caspase-8 has a
pro-apoptotic role in inflammatory renal disease,
whereas podocytic NEMO is assumed to function
as anti-apoptotic. Podocyte-specific knockout
(ko) mice for either Caspase-8 or NEMO were
generated, which both turned out to exhibit no
spontaneous renal phenotype at 15, 20 and 30
weeks of age. We now intensively characterized
both mouse lines in inflammatory renal disease.
Anti-glomerular basement membrane (GBM)-nephritis (a model of human rapidly progressive glomerulonephritis) in the NEMO line was induced in
n=16 Cre--mice (WT littermates) and n=14 Cre+mice (podoc. specif. NEMO ko). Renal function
was assesssed on days 7 and 14, renal tissue
was analyzed following sacrifice of the animals
on day 14 following disease induction. As a result,
podocytic NEMO-loss led to a significant reduction of proteinuria and albuminuria on day 7 (Fig.
1A) and renal tissues on day 14 revealed significantly increased numbers of CD3+ T-cells in the
glomeruli and renal interstitium. In contrast, the
number of renal infiltrating neutrophils and monocytes/macrophages did not change. Importantly,
the glomerular podocin expression significantly
increased on day 14 in the NEMO ko (Fig. 1B),
the GBM thickness was reduced and the number
of podocytic foot processes increased. In vitro
NEMO blocking studies in cultured conditionally
immortalized podocytes by specific siRNA confirmed the increased expression of podocin. In
summary, podocytic NEMO ko in an inflammatory renal disease model surprisingly improves
renal function at an early stage of the disease,
which is obviously mediated by protective effects
on podocyte function. In contrast and also unexpectedly, first data from anti-GBM-nephritis in the
Caspase-8 mouse line (n=22 Cre--mice and n=23
Cre+-mice) reveal a protective effect of Caspase8 in this disease.
Podocyte specific deletion of NEMO in mice leads to a marked reduction of albuminuria on day 7 (A) and an increase of podocytic podocin
expression on day 14 (B) following induction of anti-GBM-nephritis.
GCS: glomerular cross section.
IZKF Aachen Progress Report 2011
115
2.4.
Project Funding
|
Inflammation and Consequences
|
E1-3
Funding period: 01.07.2008 - 30.06.2011
Staff: SHK (Masiah D.)
Materials 2011: € 11,950
Investments/Equipment 2011: –
Pathomechanisms in late phase of acute lung injury
Uhlig S. (Institute of Pharmacology and Toxicology)
For most patients with acute lung injury (ALI)
outcome is determined within the first 7-10 days.
However, experimental work in this field has
largely focused on first 4-24 hrs of the disease
and the mechanisms that drive the disease process beyond the first day are only poorly understood. To study the subchronic phase of ALI we
used the zymosan-induced generalized inflammation, which, following an initial septic insult,
leads to multiple organ failure and lung injury at
day 14, in contrast to LPS-septicaemias which
resolve totally around day 4.
Figure 1: Gene expression profile of pulmonary
IP10-expression (fold increase) in control animals and animals treated with LPS or zymosan
(ZY) after 3 days, 7 days and 14 days.
We therefore studied lung injury induced by LPS
or zymosan, where pulmonary inflammation resolves or progresses. To identify differential gene
expression patterns in both models, we used microarray analysis (Illumina platform) of lung tissue at day d3, d7, d14 and in controls (n=4-5 per
group). C57BL/6N mice injected with zymosan
(400mg/kg) or LPS (35mg/kg) developed sepsis
in the first three days and the mortality during this
time was 41% respectively 33% in the zymosan
and the LPS group. Histological examination of
the surviving animals on day 14 showed normal
lungs in the LPS group, but pulmonary edema,
alveolar hemorrhage and increased alveolar septal thickness. In addition, polymorphonuclear cell
recruitment was apparent in the BAL fluid.
Gene array analysis showed a comparable expression pattern in the lungs of LPS- and zymosan-treated animals at d3. At d14, in LPS-treated
animals gene expression was almost normal and
only 9 genes (none of them known in inflammation) were overexpressed at least 1.5-fold.
In contrast 51 genes, mostly pro-inflammatory,
were significantly upregulated at least 1.5-fold in
the zymosan group (adjusted p-value p<0.0001).
Many upregulated genes were of inflammatory
nature, several of the interferon-a-family. As one
example Figure 1 shows the results for the chemokine IP10 (CXCL10) that became strongly upregulated in the zymosan model on day 14.
Our data suggest for the first time that proteins of
the interferon-a-family may contribute to the late
phase of acute lung injury and that proteins such
as IP10 could represent novel markers or even
therapeutic targets in treating ALI beyond day 3.
Publications
1. Matute-Bello G, G Downey, BB Moore, SD
Groshong, MA Matthay, AS Slutsky, WM
Kuebler on behalf of the Acute Lung Injury
in Animals Study Group* (2011) An Official
American Thoracic Society Workshop Report:
116
IZKF Aachen Progress Report 2011
Features and Measurements of Experimental
Acute Lung Injury in Animals. Am J Respir Cell
Mol Biol 44: 725-738.
S. Uhlig was a member of that group.
Project Funding
|
Inflammation and Consequences
|
E1-4
2.4.
Funding period: 01.07.2008 - 30.06.2011
Staff: ½ TV-L 13 (Moreno Zaldivar M.)
Materials 2011: € 1,950
Investments/Equipment 2011: –
Importance of the chemokine scavenger receptor D6 for acute
liver injury
Wasmuth H. (Department of Medicine III)
Tacke F. (Department of Medicine III)
In the first part of the project we have systematically investigated the functional importance of
the chemokine scavenger receptor D6 in different
models of liver injury. As this receptor binds many
different proinflammatory chemokines without
post-receptor signalling, we postulated that mice
with a targeted deletion of this receptor should be
more prone to acute and chronic liver injury. However, while acute hepatocyte damage was indeed
pronounced in D6 deficient mice (Berres et al.
Biol Chem 2010), these mice were not prone to
increased injury in chronic liver disease models
(inkling CCl4 injections and MCD diet). Thus, this
particular scavenger receptor appeared to be of
limited importance within the liver.
Apart from D6, another chemokine scavenger
receptor is a Duffy antigen receptor for chemokines (DARC). This receptor is expressed on red
blood cells and also scavenges numerous chemokines which are known to play an important
role within the liver (e.g. CCL2). The gene for this
receptor harbours a polymorphism which strongly
determines the concentrations of chemokines in
healthy individuals. Thus, we hypothesized that
this polymorphism should also be related to
liver injury mediated by chemokines. However,
in a large scale association study we could not
identify a significant correlation between alleles
of this SNP and histological or clinical outcomes
of hepatitis C virus infection (Lettow et al. Hum
Immunol 2011). In summary, this project revealed
that, despite its biological plausibility, chemokine
scavenger receptors appear to play only a minor
role in murine models and in humans with chronic
liver diseases.
Publications
IZKF relevant, project associated
1. Lettow I, Schmitz P, Berres ML, Müller T, Berg
T, Neumann UP, Trautwein C, Wasmuth HE
(2011) A Duffy antigen receptor for chemokines
(DARC) polymorphism which determines profibrotic chemokine serum concentrations is not
directly associated with progression of hepatitis C infection. Hum Immunol 72: 273-277 [IF
2.55]
2. Do O NT, Eurich D, Schmitz P, Schmeding M,
Heidenhain C, Bahra C, Trautwein C, Neuhaus P, Neumann UP, Wasmuth HE (2011) A
seven gene signature of the recipient predicts
progression of fibrosis after liver transplantation for hepatitis C infection. Liver Transpl, in
press [IF 3.07]
Promoting of young researcher
Doctoral Theses
Lettow, I.
2011
RWTH Aachen,
Faculty of
Medicine
A Duffy antigen receptor for chemokines (DARC)
polymorphism that determines profibrotic chemokine serum concentrations is not directly associated with progression of hepatitis C infection
IZKF Aachen Progress Report 2011
117
2.4.
Project Funding
|
Inflammation and Consequences
|
E2
Relevance of CREM a in the T-cell pathophysiology of SLE
Tenbrock K. (Department of Paediatric and Adolescent Medicine)
Interleukin 17 producing T cells represent a distinct group of T cells serving different functions
in antimicrobial defense and autoimmunity. Systemic lupus erythematosus (SLE) is the prototype
autoimmune disease in which T cells produce decreased amounts of IL-2 but increased amounts
of IL-17. Overexpression of the cAMP response
element modulator CREM_ in human SLE T cells
may represent a possible link for this antithetic
interleukin production.
In order to understand how CREM influences the
immune response in SLE as a part of this IZKF
project we generated 2 transgenic mice, one with
a constitutive overexpression of CREM_ in T
cells under control of the CD2 promoter and one
with a constitutive overexpression of CREM_ in
all hematopoietic cells under control of the vav
promoter.
The CD2 animals overexpressing CREM_ in T
cells are characterized by enhanced IL-17 and
IL-21 production and enhanced disease activity
in IL-17 dependent disease models like colitis
and contact dermatitis (manuscript under review).
Additionally these mice show enhanced disease
activity in a LPS induced lung failure model
(manuscript submitted). Furthermore we bred the
mice into a fas-/- strain. These mice show a severe
amplification of lymphoproliferation and splenomegaly with a massive expansion of pathogenic
CD4-CD8- double negative T cells (Fig. 1).
The vav-CREM animals show signs of enhanced
inflammation in animal models of contact dermatitis and experimental colitis as well. Additionally
the vav-VREM mice display an enhanced inflammatory phenotype (M1) in macrophages and decreased capacity of phagocytosis, which will be
the topic of the recently granted DFG application.
Figure 1: left: Lymphadenopathy score in fas-/- and fas-/- CREM transgenic mice in comparison to age
(weeks); right: picture of splenes of wildtype (WT), fas-/- and fas-/- CREM transgenic mice.
118
IZKF Aachen Progress Report 2011
Project Funding
|
Inflammation and Consequences
|
E2
2.4.
IZKF Aachen Progress Report 2011
119
Funding period: 01.07.2008 - 30.06.2011
Staff: 1 TV-L 9 (Maschke-Neuß K.)
Materials 2011: € 7,600
Investments/Equipment 2011: –
Publications
IZKF relevant, project associated
1. Lippe R., Ohl K., Varga G., Rauen T., Crispin
JC, Juang YT, Kürten S., Tacke F., Wolf M.,
Roebrock K., Vogl T., Verjans E., Honke N.,
Ehrchen J., Foell D., Skryabin B., Wagner N.,
Tsokos GC, Roth J., Tenbrock K., CREM_
overexpression decreases IL-2 production,
induces a TH17 phenotype and accelerates
autoimmunity, JMCB 2012, accepted for publication [IF 13.4]
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Tenbrock, K.
Regulation of the immune
response by CREM
DFG
2008-2011
2012-2014
(approved)
€ 194,000
€ 160,000
Promoting of young researcher
Doctoral Theses
Ohl, K.
2011
RWTH Aachen,
Biology
Regulation of the immune response by
CREM alpha
Honke, N.
Ongoing
RWTH Aachen,
Biology
Posttranscriptional regulation of gp130 in cells
of the immune system
Awards
Scientific award of the GKJR (Gesellschaft für Kinder-und Jugendrheumatologie), Munich 2011
2.4.
Project Funding
|
Inflammation and Consequences
|
E3
Acute glomerular injury of the kidney
Möller M. (Department of Medicine II)
In the present project, we have two major findings
regarding the pathogenesis of acute glomerular
injury in the kidney.
1. Within the first year of the funding period,
we could show definite evidence that parietal
epithelial cells (PECs) are the major cells that
form extracapillary proliferations („crescents“)
in the most dramatic form of inflammatory glomerulonephritis (rapidly progressive glomerulonephritis) (Smeets et al., JASN, 2009). This
major finding defines the activated PECs as
the actual therapeutical target to treat this dramatic inflammatory disease. The finding was
possible, because we could use our unique
inducible transgenic mouse model, which allows to label and trace PECs in glomerular
disease.
2. Our second major finding was just accepted
for publication (Sicking et al., JASN, in press).
Using our transgenic mice, we developed a
system that allows to ablate PECs in an in-
Figure 1: Schematic of the pathogenesis of cellular crescents in RPGN.
120
IZKF Aachen Progress Report 2011
ducible and specific fashion. We could show,
that a significant fraction of the PECs can be
ablated with this system. Surviving PECs became subsequently activated and started to
proliferate. Proliferation persisted beyond the
ablation period and ultimately this process perpetuated into the formation of classical crescents. This was consistent with our first major
observation that crescents are indeed formed
by activated PECs. As a side-finding, we found
that PEC ablation caused an injury within the
adjacent podocytes and a partial breach of the
glomerular filtration barrier. This interesting
finding will be further investigated in follow-up
projects (funded from an external source). In
conclusion, all major goals of this project were
achieved and published in the highest-ranking
nephrology journal.
Project Funding
|
Inflammation and Consequences
|
E3
2.4.
IZKF Aachen Progress Report 2011
121
Funding period: 01.07.2009 - 30.06.2011
Staff: ½ TV-L 13 (Sicking E.-M.)
Materials 2011: € 8,000
Investments/Equipment 2011: –
Publications
IZKF relevant, project associated
1. Sicking EM, Fuss A, Uhlig S, Jirak P, Dijkman
H, Wetzels J, Engel DR, Urzynicok T, Kriz W,
Kurts C, Ostendorf T, Floege J, Smeets B, and
Moeller MJ (2012) Subtotal Ablation of Parietal
Epithelial Cells results in Cellular Activation
and Crescent Formation. J Am Soc Nephrol;
in press [IF 8.2]
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Moeller, M.J.
The EGF System in rare glomerular EU, DLR
disease: From molecular
mechanism to therapeutics
(Rare-G)
05/201204/2015
€ 207,532
Promoting of young researcher
Doctoral Theses
Sicking, E.
Ongoing
Essen,
Veterinary
Medicine
The functional role of PECs in acute glomerular
disease
Awards
2011 Franz-Volhard Award of the German Society for Nephrology (DGfN)
2.4.
Project Funding
|
Inflammation and Consequences
|
E4
Characterisation of mechanisms of HGF/c-Met dependent
cytoprotection in hepatocytes during the liver development
and in a model of experimental hepatitis
Streetz K. (Department of Medicine III)
During the previous funding period different goals
were achieved. First we continued our experimental analysis of the pathophysiology after bileduct-ligation (BDL). An important part of this was
the characterisation of the cross-talk between
HGF/c-Met and gp130 signalling. Towards this
goal c-Met/gp130 double knockout mice were
created and underwent BDL. We observed an
early mortality of those mice, induced by a significant bacteraemia. Further analysis unravelled, that the bacterial recognition of the latter
mice was greatly impaired, thus causing the early
death of the animals.
We further developed the NASH-mouse models
in the laboratory. Here c-Met deficient mice were
treated with different NASH-inducing dietary protocols. The application of a high fat diet induced a
much stronger liver injury in c-Met deficient mice.
This ultimately resulted in a stronger activation of
matrix-producing cells and fibrosis progression.
Gene array analysis of those mice unravelled,
that numerous anti-apoptotic and fibrosis modulating genes were deregulated. Together with our
earlier data from bile-duct-ligated c-Met knockout
mice we can provide clear evidence for the antifibrotic role of the HGF/c-Met system.
We further characterised the role of c-Met during
the process of cell-selection in a model of hepatocyte transplantation in a mouse model previously
established in our laboratory. Here we show that
first c-Met is important for the selection of transplanted hepatocytes. Mice carrying a c-Met deficiency were not able to become selected after
transplantation. In the opposite, if c-Met deficient
mice were used as recipients a strong selection
of transplanted cells was observed.
Taken together we could show that c-Met regulates many cellular functions in hepatocytes under various conditions. It provides important antifibrotic signals and acts as a mandatory gene for
cell selection under the condition of chronic liver
injury.
Publications
IZKF relevant, project associated
1. Giebeler A, Brandenburg L, Kaldenbach M,
Erschfeld S, Birchmeier C, Wasmuth H, Trautwein C, Streetz KL.. Lack of hepatic c-Met
and gp130 expression is associated with an
impaired anti-bacterial response and higher
lethality after bile duct ligation
Under revision, Laboratory investigation
122
IZKF Aachen Progress Report 2011
2. Kaldenbach M, Giebeler A, Tschaharganeh
DF, Erschfeld S, Wasmuth HE, Dolle L, Floege
J, Trautwein C, Streetz KL. Hepatocyte growth
factor/c-Met signalling is important for the selection of transplanted hepatocytes.
Gut. 2012 Jan 27.
Project Funding
|
Inflammation and Consequences
|
E4
2.4.
IZKF Aachen Progress Report 2011
123
Funding period: 01.07.2008 - 31.12.2011
Staff: TV-L 13 (Giebeler A.)
½ TV-L 13
(Chaudary K., Kaldenbach M.)
Materials 2011: € 11,300
Investments/Equipment 2011: –
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Streetz, K.
Mechanisms of liver repopulation:
optimisation of hepatocyte
transplantation and use of liver
progenitor cells as donor cells
Dissecting anti-fibrotic
mechanisms of HGF/c-Met during
NASH development
€ 280,000
DFG 661/4-2
granted
DFG, subproject SFB
TTR55,
2nd period
will be applied
for
Promoting of young researcher
Doctoral Theses
Giebeler, A.
2011
University
Hospital of
Aachen
HGF/c-Met and IL-6/gp130 mediated signalling
pathways in a model of acute and chronic
cholestatic liver injury in mice
Postdoctoral lecture qualification
Giebeler, A.
Ongoing
University
Hospital of
Aachen
Experimental Therapy of liver failure
2.4.
Project Funding
|
Inflammation and Consequences
|
E5
Functional importance of the chemokin RANTES and its
receptors for fatty liver disease and obesity
Wasmuth H. (Department of Medicine III)
The overall aim of the project was dedicated to
the molecular characterization of the chemokine
RANTES (systematic name CCL5) during the
development of fatty liver disease and its related
metabolic conditions. To this end, we subjected
mice with a genetic deletion of CCL5 or its receptor CCR5 to different diets which induce liver
steatosis with or without development of obesity
in the animals. The first diet consisted of a Methionin and Cholin deficient diet which induces a
fatty liver disease with pronounced liver inflammation. Using this model, we could show that
mice deficient for the chemokine CCL5 have an
ameliorated liver phenotype and a reduced degree of liver fibrosis. Notably, improvement of
liver injury was also achieved by an antagonist to
CCL5 receptors (Met-CCL5) and was mediated
by a reduced activation of hepatic stellate cells
secondary to dampened inflammation (Berres
et al. J Clin Invest 2010). In the second model,
mice received a diet containing 60% of calories
from fat which induced marked obesity and liver
steatosis after 16 weeks of feeding. In this model,
mice deficient in either CCL5 or CCR5 displayed
a reduced liver steatosis and gained less weight
compared to their wild-type counterparts. Interestingly, mice deficient for the CCL5 receptor
CCR1 showed no phenotypical differences compared to wild-type mice. The main effect of CCL5
in this model appears to be the recruitment of
inflammatory cells into the adipose tissue which
is mediated by CCL5 secretion from adipocytes
(Nellen et al. manuscript in preparation). Overall, the results of the project strongly reinforced
the concept that chemokines are important mediators of different liver diseases and that tissue
injury might be modulated by pharmacological
chemokine antagonists.
Publications
IZKF relevant, project associated
1. Sahin H, Berres ML, Wasmuth HE (2011).
Therapeutic potential of chemokine receptor
antagonists for liver disease. Expert Rev Clin
Pharmacol. 2011 Jul;4(4):503-13.
2. Wasmuth HE, Trautwein C (2011) Prediction
of fibrosis progression in hepatitis C infection:
Are genetics ready for clinical use? J Hepatol
55: 3-4 (editorial)
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Wasmuth,
H. E.
124
Functional impotance of the
interacting chemokines CCL5 and
CXCL4 in fatty liver disease
IZKF Aachen Progress Report 2011
Else-Kröner
Fresenius
Stiftung
06/201106/2014
€ 234,000
Project Funding
|
Inflammation and Consequences
|
E5
2.4.
IZKF Aachen Progress Report 2011
125
Funding period: 01.07.2009 - 30.06.2011
Staff: TV-L 13 (Sahin H.)
Materials 2011: € 11,500
Investments/Equipment 2011: –
Promoting of young researcher
Doctoral Theses
Rüland, A.
2011
RWTH Aachen,
Faculty of
Medicine
Functional relevance of the chemokine RANTES in
liver fibrosis
Appointments to other universities
Wasmuth, H. E.
University of Rostock, Department of
Gastroenterology and Endokrinology
W3
declined
2.4.
Project Funding
|
Inflammation and Consequences
|
E6
Stress signals in aseptic inflammation
Huber M. (Institute of Biochemistry and Molecular Biology,
Department of Biochemistry and Molecular Immunology)
Inflammation is our body’s principal response
to external stressors such as injury, mechanical
stress or infection, and can also be incited by internal signals through TLR-dependent pathways
and/or activated leukocytes. While microbial
infections have been examined in great detail,
comparatively less is known about inflammation
caused by aseptic (other words used are non-infectious or sterile) stimuli. In this joint project we
are therefore examining the common principles
that rule aseptic inflammation (see Figure 1). In
doing so we are studying (i) signaling responses
to stress, (ii) the cardinal symptoms of inflammation, (iii) and the regulation of inflammation.
Within each of these three broad areas we are
focusing ourselves on one particular problem: (i)
the role of MAP-kinases in stress-induced and
inflammation-related signaling, (ii) the mechanisms of leukocyte transmigration into stressed
tissues and (iii) the regulation of these processes
by endogenous anti-inflammatory mechanisms.
Obviously, interactions between these areas do
exist and the chosen topics allow the integration
of studies that are mainly cell-based (project area
A) with those addressing complex organ injury in
animal models (project area B). Because these
interests are shared by all groups of our network
“Stress signals in aseptic inflammation”, mutual
interactions are already well developed and are
intended to further grow to the benefit of the entire inflammation focus at the University Hospital
Aachen.
Publications
IZKF relevant, project associated
1. Zimmermann HW, Seidler S, Gassler N, Nattermann J, Luedde T, Trautwein C, Tacke F
(2011) Interleukin-8 Is Activated in Patients
with Chronic Liver Diseases and Associated
with Hepatic Macrophage Accumulation in Human Liver Fibrosis. PLoS One. 6(6): e21381
126
IZKF Aachen Progress Report 2011
2. Zimmermann HW, Tacke F (2011) Modification of chemokine pathways and immune cell
infiltration as a novel therapeutic approach in
liver inflammation and fibrosis. Inflamm Allergy
Drug Targets. 10(6):509-36.
Project Funding
|
Inflammation and Consequences
|
E6
2.4.
IZKF Aachen Progress Report 2011
127
Funding period: 01.07.2011 - 30.06.2014
Materials/Travel expenses 2011: € 76,500
Investments/Equipment 2011: –
3. Heymann F, Hammerich L, Storch D, Bartneck
M, Huss S, Rüsseler V, Gassler N, Lira SA, Luedde T, Trautwein C, Tacke F. (xxxx) Hepatic
macrophage migration and differentiation critical for liver fibrosis is mediated by the chemokine receptor CCR8. Hepatology (in press)
Actually only some of our preliminary work that
was outlined in our initial proposal was published
(without IZKF acknowledgement) in an abstract
and an original publication.
1. Borkham-Kamphorst E, Drews F, Weiskirchen
R. (2011) Induction of lipocalin-2 expression
in acute and chronic experimental liver injury
moderated by pro-inflammatory cytokines interleukin-1` through nuclear factor-gB activation. Liver Int 31:656-665. [IF 2.99]
In addition, we have published a comment which
acknowledges this IZKF project. The corresponding reference is:
1. Bergmann C, Weiskirchen R. (2011) It’s not all
in the cilium, but on the road to it: Genetic interaction network in polycystic kidney and liver
diseases and how trafficking and quality control matter’. J Hepatol Nov 28. [Epub ahead of
print]. [IF 9.334]
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Huber, M.
Lüscher, B.
Analysis of tolerance and
reprogramming mechanisms
in mast cells
DFG HU794/9-1 applied
NA
Müller-Newen, Persistent activation of STAT
DFG, TransreG.
transcription factors in inflammatory gio-SFB TRR
cytokine pathways and modulation 116
of their subcellular distribution by
cross-talk mechanisms.
07/201206/2016
€ 100,000
p.a.
Tenbrock, K.
Regulation of the immune
response by CREM
DFG
2008-2011
2012-2014
(approved)
€ 194,000
€ 160,000
Ludwig, A.
Role of the metalloproteinases
ADAM10 and ADAM17 in acute
lung inflammation
DFG Lu869/5-1 03/201103/2014
€ 480,000
Promoting of young researcher
Diploma Theses
Dohmen, M.
2011
RWTH Aachen,
Medical School
Investigation of the TLR4-induced autophagy pathway downstream of p38: Connection to cell cycle
Levikova, M.
2011
RWTH Aachen,
Faculty 1
Mechanism of endotoxin tolerance in mast cells
Kläner, O.
Ongoing
RWTH Aachen,
Faculty 1
IL-10-induced tolerance in mast cells: mechanisms
and effects
Martincuks, A.
Ongoing
RWTH Aachen,
Faculty 1
Cross-talk and subcellular localization of NF-gB
and STAT3
2.4.
Project Funding
|
Inflammation and Consequences
|
E6
Wiener, A.
Ongoing
RWTH Aachen,
Biology
Der Einfluss des Transkriptionsfaktors CREMa
auf die B-Zell-Aktivierung und die B-Zell-T-Zell
Interaktion in Keimzentren der Milz.
Asimakopoulos,
Anastasia.
Ongoing
RWTH Aachen,
Faculty 1
LCN2 in inflammatory liver disease
Dohmen, M.
Ongoing
Medical School,
RWTH Aachen
Investigation of the TLR4-induced autophagy
pathway downstream of p38: Connection to cell
cycle
Kuhny, M.
2011
University of
IL-1-type cytokines and mast cells: Induction of
Freiburg,
proinflammatory responses and a non-canonical
Faculty of biology release mechanism
Poplutz, M.
Ongoing
RWTH Aachen,
Faculty 1
Reprogramming of the allergic mast cell response
by low-dose endotoxin
Rinis, N.
Ongoing
RWTH Aachen,
Faculty 1
Anti-inflammatory activity of persistently activated
STAT3
Ohl, K.
2011
RWTH Aachen,
Biology
Regulation of the immune response by CREM
alpha
Honke, N.
Ongoing
RWTH Aachen,
Biology
Posttranscriptional regulation of gp130 in cells of
the immune system
Hess, F. M.
Ongoing
RWTH Aachen,
Biology
Role of the metalloproteinases ADAM10 and
ADAM17 for leukocyte migration
Lux, St.
Ongoing
RWTH Aachen,
Faculty 10
Functional analysis of CCN proteins in hepatic
fibrogenesis
Bultmann, C.
Ongoing
RWTH Aachen,
Faculty 10
Regulation and function of the LIM domain proteins
CRP2 and FHL2 in experimental models of liver
injury
Alexi, P. H.
Ongoing
RWTH Aachen,
Faculty 1
The role of TGF-` and PDGF isoforms in inflammatory liver diseases
Boaru, S. G.
Ongoing
RWTH Aachen,
Faculty 1
Expression analysis of inflammasome components
in models of inflammatory liver disease
Nagel, P.
Ongoing
RWTH Aachen,
Medicine
In vitro and in vivo assessment of ADAM10 and
ADAM17 function by inhibitory prodomains
Doctoral Theses
Awards
Tenbrock (E6-7): Scientific award of the GKJR (Gesellschaft für Kinder-und Jugendrheumatologie),
Munich 2011
128
IZKF Aachen Progress Report 2011
Project Funding
|
Inflammation and Consequences
|
E6-1
2.4.
Funding period: 01.07.2011 - 30.06.2014
Staff: ½ TV-L 13 (Dohmen M.)
Materials 2011: € 6,500
Investments/Equipment 2011: –
Investigation of the LPS/TLR4-induced autophagy pathway
downstream of p38: Connection to cell cycle regulators
Vervoorts J., Lüscher B. (Department of Biochemistry and Molecular Biology)
The elimination of invading pathogens by the
innate immune system is in part mediated by
the intracellular autophagy-mediated destruction of these pathogens. The signalling mechanisms activating this destruction pathway are
dependent on the activation of toll-like receptors
(TLR), which relay the signal to the MAPK p38.
The signalling events downstream of p38 linking
TLR to the autophagic machinery are presently
unknown. We postulate that a cascade consisting of MSK1, p27 and cyclin Y/CDK16 is required
to activate autophagy downstream of p38. Moreover we suggest that cyclin Y/CDK16 provides a
direct link to the autophagic machinery due to its
interaction with ATG3 and ATG12.
During the first 6 months of our project we were
able to confirm the published observation, by
using specific p38 inhibitors, that the activation
of p38 in response to LPS is responsible for the
induction of autophagy in macrophages. As a direct downstream target of p38 we could define
that MSK1 but not RSK1 is responsible for the
induction of autophagy (Fig. 1). Furthermore we
observed by using siRNA against MSK1 and
p27 that both proteins are involved in the regulation of autophagy. To investigate the proposed
phosphorylation of p27 at Thr198 by MSK1 we
generated a phosphor-Thr198 specific antibody
in cooperation with Elisabeth Kremmer, HZI
München.
In the second part of our project we started to
investigate the function of the cyclin Y/CDK16
kinase complex. To identify new substrates of cyclin Y/CDK16 we generated baculoviral derived
cyclin Y/CDK16, which we will use to screen a
high-density protein microarray covering over
8000 full-length human proteins (ProtoArray,
Invitrogen). To find a new interaction partner of
cyclin Y/CDK16, we established a TET-inducible
HE293T cell line expressing TAP-tagged CDK16
and Flag-cyclin Y.
Figure 1: The MAPKs p38 and MSK1 take part in the induction of autophagy in LPS treated macrophages. A) RAW264.7 cells
were treated with LPS for the indicated time and the induction of autophagy were monitored by the formation of LC3-II dots.
BIRB796 was used as p38 inhibitor an H89 as MSK1 inhibitor B) Quantification of the LC3-II punctuation in A.
IZKF Aachen Progress Report 2011
129
2.4.
Project Funding
|
Inflammation and Consequences
|
E6-1
Publications
IZKF relevant, project associated
1. Lüscher B, Vervoorts J, Regulation of gene transcription by the oncoprotein MYC (2012) Gene, in Press
[IF: 2,26]
Promoting of young researcher
Diploma Theses
Dohmen, M.
2011
RWTH Aachen,
Medical School
Investigation of the TLR4-induced autophagy
pathway downstream of p38: Connection to cell
cycle
Ongoing
RWTH Aachen,
Medical School
Investigation of the TLR4-induced autophagy
pathway downstream of p38: Connection to cell
cycle
Doctoral Theses
Dohmen, M.
130
IZKF Aachen Progress Report 2011
Project Funding
|
Inflammation and Consequences
|
E6-2
2.4.
Funding period: 01.07.2011 - 30.06.2014
Staff: ½ TV-L 13 (Kuhny M.)
Materials 2011: € 6,000
Investments/Equipment 2011: –
Reprogramming of the allergic mast cell response by low-dose
endotoxin
Huber M. (Institute of Biochemistry and Molecular Biology,
Department of Biochemistry and Molecular Immunology)
The phenomenon of endotoxin (lipopolysaccharide (LPS)) tolerance (ET) is known as an incapability of cells to respond to high-dose LPS challenge after being exposed to low doses of LPS.
Our preliminary findings showed that ET can be
induced in mast cells (MCs), effector cells that
are not only important in allergy but also in initiation and maintenance of innate and adaptive
immune responses. It has been shown that ET
is a result of gene reprogramming and immunomodulation in macrophages and monocytes,
involving complex epigenetic mechanisms. Altered TLR4 signaling has also been observed
in endotoxin tolerant monocytes and several
mechanisms were suggested to be decisive for
the development of ET. However, so far there is
no knowledge about ET mechanisms in MCs.
Induction of ET was investigated in mouse bone
marrow-derived MCs (BMMCs). RNA expression
of the IL-6 and TNF-_ was dramatically reduced
in LPS-tolerant cells, correlating with only basal
NF B p65 and p50 binding to the promoters of
these cytokine genes. On the chromatin level,
no changes in histone H3 lysine 4 trimethylation
(H3K4me3) could be detected in the promoter
regions. However, the trimethylation level of histone H3 lysine 9 (H3K9me3) decreased after LPS
stimulation of naïve BMMCs, allowing the binding
of p65 and p50, while it was sustained in tolerant
cells. The analysis of upstream signaling events
showed, that the nuclear translocation of p65
is almost absent in tolerant BMMCs upon LPS
stimulation, which can be explained by reduced
I B_ (inhibitor of NF B) degradation, caused by
almost inactive IKK` (I B kinase). The activation
of MAPK signaling was also impaired in tolerant
BMMCs. Intriguingly, cytokine production as well
as NF B signaling could be almost fully restored
by antigen stimulation of tolerant BMMCs, indicating that ET is not a state of total unresponsiveness and epigenetic silencing in MCs. In our
further experiments we will define LPS tolerance
mechanisms in greater molecular detail and unravel signaling pathways and mechanisms which
are responsible for the escape from tolerance of
antigen-triggered mast cell activation.
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Huber, M.
Lüscher, B.
Analysis of tolerance and
reprogramming mechanisms in
mast cells
DFG HU794/9-1 applied
NA
IZKF Aachen Progress Report 2011
131
2.4.
Project Funding
|
Inflammation and Consequences
|
E6-2
Promoting of young researcher
Diploma Theses
Rüland, A.
2011
RWTH Aachen,
Faculty of
Medicine
Functional relevance of the chemokine RANTES in
liver fibrosis
Levikova, M.
2011
RWTH Aachen,
Faculty 1
Mechanism of endotoxin tolerance in mast cells
Kläner, O.
Ongoing
RWTH Aachen,
Faculty 1
IL-10-induced tolerance in mast cells: mechanisms
and effects
Kuhny, M.
2011
University of
IL-1-type cytokines and mast cells: Induction of
Freiburg,
proinflammatory responses and a non-canonical
Faculty of Biology release mechanism
Poplutz, M.
Ongoing
RWTH Aachen,
Faculty 1
Doctoral Theses
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Reprogramming of the allergic mast cell response
by low-dose endotoxin
Project Funding
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Inflammation and Consequences
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E6-3
2.4.
Funding period: 01.07.2011 - 30.06.2014
Staff: ½ TV-L 13 (Rinis N.)
Materials 2011: € 6,000
Investments/Equipment 2011: –
Anti-inflammatory activity of persistently activated STAT3
Müller-Newen G. (Institute of Biochemistry and Molecular Biology)
STAT3 is known as an anti-inflammatory transcription factor in macrophages and T-cells. Persistent activation of STAT3 together with NF- B
contributes to the progression from chronic inflammation to cancer. Recently, a constitutively
active mutant of the IL-6 receptor subunit gp130
(ca-gp130) has been identified that is insensitive
to the feedback inhibition through SOCS3 and
therefore leads to persistent STAT3 activation.
In this project the anti-inflammatory activity of
ca-gp130 will be explored in comparison to the
STAT3-activating cytokines IL-6 and IL-10.
Stable cell lines were generated in which the
expression of a fluorescently labelled ca-gp130
(ca-gp130-YFP) can be induced by the addition
of doxycycline. We found that signalling of cagp130 differs significantly from cytokine-induced
signalling of wild type gp130. IL-6, a cytokine
signalling through gp130, transiently activates
STAT3, STAT1 and ERK1/2. In contrast ca-gp130
leads to a persistent STAT3 activation but fails to
activate STAT1 and ERK1/2. It will be interesting
to explore the anti-inflammatory potential of this
skewed ca-gp130 signalling. For this purpose,
macrophage cell lines will be transfected to study
the effect of ca-gp130 signalling on pro-inflammatory cytokine release.
Moreover, ca-gp130 has been transferred into a
system that allows the tissue specific and inducible expression of ca-gp130-YFP in mice (coop.
with Liedtke/Trautwein). Transgenic mice have
been generated and induction of ca-gp130-signalling by doxycycline has been shown in primary
hepatocytes from these mice. Further studies will
evaluate the impact of ca-gp130 in inflammatory
diseases of the liver (Liedtke/Trautwein) and the
kidney (Ostendorf/Floege).
Figure 1: Skewed signalling of ca-gp130 might result from intracellular signals emanating from Golgi/ER compartments.
Publications
IZKF relevant, project associated
The project is funded since 6 months. Therefore, there are no publications referring to IZKF funding yet.
IZKF Aachen Progress Report 2011
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Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Müller-Newen, Persistent activation of STAT
DFG,
07/2012G.
transcription factors in inflammatory Transregio-SFB 06/2016
cytokine pathways and modulation TRR 116
of their subcellular distribution by
cross-talk mechanisms.
€ 100,000
p.a.
Promoting of young researcher
Master Theses
Martincuks, A.
Ongoing
RWTH Aachen,
Faculty 1
Cross-talk and subcellular localization of NF-gB
and STAT3
Ongoing
RWTH Aachen,
Faculty 1
Anti-inflammatory activity of persistently activated
STAT3
Doctoral Theses
Rinis, N.
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IZKF Aachen Progress Report 2011
Project Funding
|
Inflammation and Consequences
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E6-4
2.4.
Funding period: 01.07.2011 - 30.06.2014
Staff: ½ TV-L 13 (De Santis R.)
Materials 2011: € 6,000
Investments/Equipment 2011: –
Characterization of miRNAs as modulators of TLR4-mediated
MAPK signaling
Ostareck –Lederer A. (Experimental Research Unit, Department of Intensive Care)
Ostareck D. H. (Experimental Research Unit, Department of Intensive Care)
Macrophages recognize microbial pathogens
mainly through toll-like receptors (TLRs). LPS
binding to TLR4 triggers downstream signaling cascades, which include mitogen activated
kinases (MAPKs), like JNK and p38 and finally
merge to activate the expression of pro- and
anti-inflammatory cytokines. The expression of
kinases and their modulators involved in these
processes is regulated both on the transcriptional
and post-transcriptional level. Our project focuses on the latter, particularly the identification and
functional characterization of miRNAs that control the stability and translation of mRNAs, which
encode TLR4 downstream proteins. Through
deep sequencing of cDNA libraries from murine
macrophages (RAW 264.7) we could identify
Fig. 1
(A) RAW 264.7 cells were treated with 10 ng/ml LPS for up to 6 hours, after lysis cytoplasmic extract was prepared, total RNA
and miRNAs were isolated.
(B) LPS induced synthesis of mRNAs encoding pro- and anti-inflammatory cytokines was analyzed by RT-PCR and agarose
gel electrophoresis.
(C) Northern blot analysis of miRNA 146a, 146b and 155 identified as upregulated after LPS induction in our deep-sequencing
approach and experimentally (Taganov et al. PNAS. 2006; Tili et al., J. Immunol. 2007).
IZKF Aachen Progress Report 2011
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2.4.
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Inflammation and Consequences
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E6-4
annotated and novel miRNAs differentially expressed in response to LPS. In silico target prediction employing databases like TargetScan led
to the identification of miRNAs that potentially target mRNAs of TLR4 pathway proteins. In order
to verify the expression of specific miRNAs that
emerged from the cloning analysis in untreated
and LPS stimulated RAW 264.7 cells, we will perform Northern blot analyses and qRT-PCR (Fig.
1). For this purpose we established both assays
for miRNA 146a, 146b, and 155, which are induced by LPS (Taganov et al., PNAS, 2006; Tilin
et al., J. Immunol., 2007) and could be verified in
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IZKF Aachen Progress Report 2011
our deep sequencing approach. Based on these
experiments we will proceed with the functional
characterization of interesting miRNAs through
the use of in vitro translation assays employing
luciferase reporter mRNAs. Furthermore, to test
whether verified miRNAs are efficiently bound
by functional RNA induced silencing complexes
(RISCs), we isolate these complexes by Ago-2
affinity purification. Currently we are in the process to establish protocols to isolate RISC-associated mRNAs.
Project Funding
|
Inflammation and Consequences
|
E6-5
2.4.
Funding period: 01.07.2011 – 30.06.2014
Staff: ½ TV-L 13
(Hermanns N., Ehedego H.)
Materials 2011: € 9,500
Investments/Equipment 2011: –
Relevance of death receptors for NEMO-dependent hepatitis
Trautwein Ch. (Department of Medicine III)
Death receptor-mediated hepatocyte apoptosis is
implicated in a wide range of liver diseases including viral and alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic
liver injury as well as cancer. Deletion of NF-gB
essential modulator in hepatocytes (Nemo¨hepa)
causes the spontaneous development of hepatocellular carcinoma preceded by steatohepatitis
in mice and thus serves as an excellent model
for the progression from chronic hepatitis to liver
cancer. In the present study we aim to dissect the
death-receptor mediated pathways that contribute
to liver injury in Nemo¨hepa mice as our recent data
demonstrated that Nemo¨hepa/Casp8¨hepa.double
knockout mice show less apoptosis in their livers.
Therefore in the current project we generated
Nemo¨hepa/TRAIL-/- and Nemo¨hepa/TNFR1-/- animals to understand the relevance of distinct TNF
family members for disease progression. Our first
results suggest that Nemo¨hepa/TNFR1-/- animals
in contrast to Nemo¨hepa/TRAIL-/- show a reduced
phenotype concerning liver injury in 8 week old
animals.
Figure 1: see enclosed, showing that 8 week
old Nemo¨hepa/TNFR1-/- animals in contrast to
Nemo¨hepa/TRAIL-/- and Nemo¨hepa mice show
reduced transaminases (ALT values)
IZKF Aachen Progress Report 2011
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2.4.
Project Funding
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Inflammation and Consequences
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E6-6
Funding period: 01.07.2011 - 30.06.2014
Staff: ½ TV-L 13 (Lex D.)
Materials 2011: € 8,500
Investments/Equipment 2011: –
The role of neuropeptide Y and the sympathetic nervous
system in the regulation of ventilator-induced lung injury
Uhlig S. (Institute of Pharmacology and Toxicology)
Ventilator-induced lung injury (VILI) is a major
complication in the treatment of patients with the
acute respiratory distress syndrome. Activation
of pro-inflammatory pathways is considered as a
major explanation for this finding. The underlying
regulation by the sympathetic nervous system
(SyNS) has received relatively little attention.
Therefore we will explore the role of the SyNS
and its relation to its co-transmitter NPY in VILI.
As part of this project, we have developed a novel
model of VILI. Mice are ventilated with a defined
gas-mixture for 7h with a Hugo Sachs Midivent
ventilator with 30 mL/kg and airway pressures
(pao) always below 34 cmH2O. Lung mechanics
Figure 1: Lung function. Murine pulmonary compliance after 7h of
mechanical ventilation with a tidal volume of 8 mL/kg or 30 mL/kg (pao
< 34 cmH2O). Data are expressed as mean ± SD, n = 4.
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IZKF Aachen Progress Report 2011
are assessed with a flow transducer, a pressure
transducer and end-tidal CO2 with a capnograph.
A catheter in the Arteria carotis communis is used
to monitor on-line blood pressure and to supply
volume. Further instrumentations are a pulse
oxymeter and a 3 lead ECG. This set-up allows
measurement of dynamic compliance, pulmonary
resistance, maximal tracheal pressure, body temperature, heart rate, arterial oxygen saturation,
systolic, diastolic and mean arterial blood pressure and end-tidal carbon dioxide. In comparison
to control animals (ventilated with 8 mL/kg), mice
ventilated with 30 mL/kg (with pao < 34 cmH2O)
showed decreasing pulmonary compliance,
hypoxemia (paO2/fiO2 230 vs. 530 mmHg) and
edema formation (wet/dry-ratio 6.7 vs. 4.9), while
arterial blood pressure and heart rate remained
stable over the whole period of mechanical ventilation. Currently we are studying the concentrations of sympathetic transmitters and co-transmitters, and inflammatory cytokines/chemokines in
the lavage fluid and in the circulation. We will try
to prevent lung injury pharmacologically by blocking Y1-receptors or adrenergic _2-receptors; vice
versa, we will do experiments to enhance lung
injury by administration of Y1-receptor-agonist or
_2-receptor-agonist. The role of sympathetic denervation on lung injury and adrenergic co-transmitter release will be examined in animals with
sympathetic denervation induced by reserpine.
These studies will allow us to define the role of
the sympathetic nervous system and its co-transmitter NPY in ventilator-induced lung injury.
Project Funding
|
Inflammation and Consequences
|
E6-7
2.4.
Funding period: 01.07.2011 - 30.06.2014
Staff: 32 h TV-L 9 (Bierwagen J.)
Materials/Travel expenses 2011: € 5,500
Investments/Equipment 2011: –
Relevance of CREM_ for the T cell pathophysiologie in SLE
Tenbrock K. (Department of Paediatric and Adolescent Medicine)
The cAMP Response Element Modulator
(CREM) _ binds to promotors of genes with
cAMP response elements (CRE) and regulates
transcription via a chromatin-dependent mechanism. CREM_ is important for the T cell pathophysiology of systemic lupus erythematosus
(SLE) and suppresses interleukin 2 (IL-2) transcription, leading to T cell anergy and reduced
activation– induced cell death with persistence
of memory T cells, which stimulate autoreactive
B cells via CD40L. We generated a transgenic
mouse overexpressing CREM_ under control of
a T cell specific CD2 promoter. As expected, this
mouse shows reduced IL-2 production, but enhanced IL-17, IL-21 and CXCR5 transcription, as
well as enhanced disease activity in several models of inflammation. Furthermore, when crossed
into the Fas -/-mrl/lpr SLE background, the CD2CREM_ transgenic mice show a massive progression of lymphadenopathy. For this funding
period following goals are planned:
1. We will identify targets of CREM_ in SLE T
cells via chromatin-immunoprecipitation and
hybridization towards a promotor-array (ChIP
on Chip).
2. We will decipher the exact mechanism of the
enhanced IL-17 and IL-21 production and enhanced occurrence of CXCR5+ follicular helper
cells within the CD2-CREM_ transgenic mice.
3. We will breed CD2 CREM_ Fas -/- mice into
a CXCR5 -/- background to reverse lymphadenopathy and T cell migration into the kidneys.
Regar ding aim 1 we are still in the recruitment
phase. Regarding aim 2 we have found that
CREM directly activates the IL-17 promoter and
the CXCR5 promoter resulting in an enhanced B
cell help with the occurrence of activated B cells
and autoantibody production (Fig 1). Regarding
aim 3 fas-/-CXCR5-/- mice are currently bred, we
will mate them with CD2-CREM mice as soon
as we get the latter ones on a Bl/6 background
from our collaborators at Harvard (within the next
6 months).
Fig. 1: Enhanced expression of CD19+GL-7+ activated B cells in
lymph nodes of fas-/- CREM transgenic mice compared to fas-/- mice.
Publications
IZKF relevant, project associated
1. CREM_ overexpression decreases IL-2 production, induces a TH17 phenotype and accelerates autoimmunity, Ralph Lippe, Kim Ohl,
Georg Varga, Thomas Rauen, Jose C. Crispin,
Yuang–Taung Juang, Stefanie Kürten, Frank
Tacke, Marc Wolf, Kirsten Roebrock, Thomas
Vogl, Eva Verjans, Nora Honke, Jan Ehrchen,
Dirk Foell, Boris Skryabin, Norbert Wagner,
George C. Tsokos, Johannes Roth, Klaus Tenbrock, JMCB 2012, accepted for publication
[IF 13.4]
IZKF Aachen Progress Report 2011
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2.4.
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Inflammation and Consequences
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E6-7
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Tenbrock, K.
Regulation of the immune
response by CREM
DFG
2008-2011
2012-2014
(approved)
€ 194,000
€ 160,000
Promoting of young researcher
Diploma Theses
Wiener, A.
Ongoing
RWTH Aachen,
Biology
The influence of CREM alpha on B cell activation
and B cell/ T cell interations in germinal centers of
the spleen
Ohl, K.
2011
RWTH Aachen,
Biology
Regulation of the immune response by CREM
alpha
Honke, N.
Ongoing
RWTH Aachen,
Biology
Posttranscriptional regulation of gp130 in cells of
the immune system
Doctoral Theses
Awards
Scientific award of the GKJR (Gesellschaft für Kinder-und Jugendrheumatologie), Munich 2011
140
IZKF Aachen Progress Report 2011
Project Funding
|
Inflammation and Consequences
|
E6-8
2.4.
Funding period: 01.07.2011 - 30.06.2014
Staff: ½ TV-L 13
Materials 2011: € 7,500
Investments/Equipment 2011: –
Analysis of molecular mechanisms of cellular communication
during initiation of inflammatory responses following acute
liver injury by two-photon microscopy
Tacke F. (Department of Medicine III)
Martin Ch. (Institute of Pharmacology and Toxicology)
The major aim of this project is to analyze molecular mechanisms of cellular communication during
the initiation of inflammatory responses following
acute liver injury by novel highly sophisticated invivo imaging technologies. Over the last year we
were able to successfully establish a long-term
intravital imaging system using two-photon laser
scanning microscopy (TPLSM), imaging toxic
liver damage induced by a single i.p. injection of
carbon tetrachloride (CCl4). Time course experiments were performed over a period of 3-6 hrs
depending on the life-time of the individual animal in series of 1-2 hrs per sequence. For initial
experiments genetically tagged animals carrying
eGFP under different chemokine receptor promoters such as CX3CR1 and CXCR6 were used,
imaging homo- as well as heterozygous animals
in time steps of 0, 12, 24, 36 and 48 hrs after CCl4
treatment. Imaging was also performed on redas well as cyan-fluorescent cells derived from
either DsRed or eCFP donor animals, setting up
the system for 3-colour time lapse imaging which
will be used throughout the further course of this
study. To allow stable long term imaging, we also
successfully implemented tracheotomy and triggered imaging to provide high quality imaging as
well as long-term survival of the animals. The surgical protocols for preparing and embedding the
Figure 1: Intravital-Multiphoton still images taken from time lapse videos of CX3CR1 and CXCR6 animals with and without CCl4
treatment to induce toxic liver damage.
A Sample images taken from a series of 45min derived from an untreated CXCR6 mouse to show cellular traffic in the sinusoidal vascular system with a time difference of 4min.
B Images of CXCR6 mice treated with a single injection of 0.4mg/g CCl4 i.p taken after 0, 12, 24 and 36 hrs.
C Images of CX3CR1 mice treated with a single injection of 0.4mg/g CCl 4 i.p taken after 0, 12, 24 and 36 hrs. Please note the
massive accumulation of eGFP+ monocytes/macrophages in the injured liver.
IZKF Aachen Progress Report 2011
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E6-8
liver used in the trial phase were further refined,
a step also critical for high quality long-term imaging. Further upgrades are currently being built
and will include a custom-made thermo-controlled
mouse-embedding unit to ensure maximum control of the environmental and physiological conditions (humidity, temperature). Data processing
and video conversion procedures of the raw data
have been established to a point to currently al-
low descriptive as well as initial statistical analysis
of time lapse series; further analysis procedures
are currently being developed and tested. This
set-up now allows experiments to be conducted
in homeostatic and injury conditions with different
transgenic mice to identify crucial molecular and
cellular mediators in the initiation of liver inflammation in vivo.
Publications
IZKF relevant, project associated
1. Zimmermann HW, Seidler S, Gassler N, Nattermann J, Luedde T, Trautwein C, Tacke F
(2011) Interleukin-8 Is Activated in Patients
with Chronic Liver Diseases and Associated
with Hepatic Macrophage Accumulation in Human Liver Fibrosis. PLoS One. 6(6): e21381
2. Zimmermann HW, Tacke F (2011) Modification of chemokine pathways and immune cell
infiltration as a novel therapeutic approach in
142
IZKF Aachen Progress Report 2011
liver inflammation and fibrosis. Inflamm Allergy
Drug Targets. 10(6):509-36.
3. Heymann F, Hammerich L, Storch D, Bartneck
M, Huss S, Rüsseler V, Gassler N, Lira SA, Luedde T, Trautwein C, Tacke F. (xxxx) Hepatic
macrophage migration and differentiation critical for liver fibrosis is mediated by the chemokine receptor CCR8. Hepatology (in press)
Project Funding
|
Inflammation and Consequences
|
E6-9
2.4.
Funding period: 01.07.2011 - 30.06.2014
Staff: ½ TV-L 13 (Hess F. M.)
Materials 2011: € 7,500
Investments/Equipment 2011: –
Role of the metalloproteinase ADAM10 in acute and chronic
inflammatory processes in the lung
Ludwig A. (Institute of Pharmacology and Toxicology)
The endothelial layer is the first barrier for leukocytes entering the inflamed lung from the blood
stream. This process involves several endothelial
surface molecules, including integrins, selectins,
junction molecules (e.g. JAM-A and VE-cadherin)
and transmembrane chemokines (e.g. CX3CL1)
that undergo ectodomain shedding by the disintegrins and metalloproteinases (ADAM) 10 and
ADAM17. We found that ADAM17 is critically involved in endothelial barrier function, edema formation, cytokine secretion and leukocyte recruitment in endotoxin-induced acute lung injury (ALI)
in mice. The role of ADAM10 in these responses
remains to be studied in more detail.
ALI was induced by intranasal LPS-challenge of
mice. The role of ADAM10 was studied by intranasal treatment with GW280264X blocking both
ADAM10 and 17 or GI254023X preferentially
blocking ADAM10. Mice were analyzed after 4 h
and 24 h of LPS-challenge. Bronchalveolar lavage
(BAL) protein content and wet-dry-ratio of lung tissue served as markers for vascular leakage and
edema formation. BAL fluid was investigated for
IL-6, TNF_, JAM-A, CX3CL1, VE-cadherin and
KC release. Neutrophil recruitment to the alveolar
space and the lung tissue was measured by flow
cytometry. Combined inhibition of both ADAM10
and ADAM17 by GW280264X as well as preferential inhibition of ADAM10 by GI254023X profoundly reduced edema formation, protein efflux,
cytokine production and leukocyte recruitment in
LPS-induced ALI suggesting critical involvement
of ADAM10. Since ADAM17 could still act independently in this setting, the role of endothelial
ADAM17 was analyzed in Tie2-Adam17-/- mice
(see report of the IZKF research group). In these
animals, all the above parameters of ALI were
profoundly reduced demonstrating that both
ADAM10 and ADAM17 independently act as
proinflammatory proteases in LPS-induced ALI.
ADAM10 and ADAM17 were further analyzed in
primary human lung microvascular endothelial
cells (HMVEC) by either pharmacological inhibition or transcriptional silencing of the proteases.
HMVEC were studied for ADAM mRNA and
protein expression, permeability changes and
shedding of JAM-A, VE-cadherin and CX3CL1
in response to LPS stimulation and analyzed for
IL-8-induced neutrophil transmigration. These in
vitro experiments with HMVEC showed that both
ADAM10 and 17 contributed to endothelial permeability and neutrophil transmigration. This effect was correlated to the shedding of endothelial
ADAM10 substrates (VE-cadherin) and ADAM17
substrates (JAM-A) involved in the regulation of
endothelial permeability towards plasma proteins
and leukocytes.
Thus, endothelial ADAM10 and ADAM17 are
independently involved in the regulation of vascular permeability, cytokine production and leukocyte recruitment during endotoxin-induced
ALI. Notably, ADAM10 and ADAM17 do not only
shed proinflammatory mediators but also generate soluble growth factors (e.g. TGF_, HB-EGF
and amphiregulin) and mediate processing of
Notch and thereby modulate tissue regeneration and angiogenesis. We therefore propose
that both ADAM10 and ADAM17 hold different
roles in chronic lung inflammation. As a model
of chronic lung inflammation we are currently applying bleomycin intratracheally to mice to induce
chronic lung inflammation and fibrosis in the lung.
Tie2-Adam10-/- mice have been generated for the
study of endothelial ADAM10 in this model. Corresponding experiments with Tagln-Adam10-/- mice
and vav-Adam10-/- mice will follow to study the
role of smooth muscle and leukocyte ADAM10,
respectively.
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Inflammation and Consequences
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Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Ludwig, A.
Role of the metalloproteinases
ADAM10 and ADAM17 in acute
lung inflammation
DFG Lu869/5-1 03/201103/2014
€ 480,000
Promoting of young researcher
Doctoral Theses
144
Hess, F. M.
Ongoing
RWTH Aachen,
Biology
Role of the metalloproteinases ADAM10 and
ADAM17 for leukocyte migration
Nagel, P.
Ongoing
RWTH Aachen,
Medicine
In vitro and in vivo assessment of ADAM10 and
ADAM17 function by inhibitory prodomains
IZKF Aachen Progress Report 2011
Project Funding
|
Inflammation and Consequences
|
E6-10
2.4.
Funding period: 01.07.2011 - 30.06.2014
Staff: ½ TV-L 13 (Kaitovic A.)
Materials 2011: € 7,500
Investments/Equipment 2011: –
Platelet-Derived Growth Factors in acute kidney injury
Ostendorf T. (Internal Medicine II)
Floege J. (Internal Medicine II)
Acute kidney injury (AKI) is an enormous worldwide problem with high mortality. Effective therapeutic strategies are lacking. We previously
identified key roles of Platelet-Derived Growth
Factor (PDGF) isoforms in chronic kidney disease (CKD). In contrast, the role of PDGF in
AKI is virtually unknown. We hypothesize that in
AKI tubular cell stress and organ damage activate the PDGF system that –depending on the
chronicity– will lead to either renal regeneration,
or chronic organ damage. Importantly, PDGFadministration would then be beneficial in AKI
whereas its inhibition is beneficial in CKD. Here
we will therefore test the novel hypothesis, that
PDGF-B, -C and/or -D mediate renal regeneration in AKI. Specifically, we will 1) characterize
the renal expression pattern of PDGF isoforms
and their receptors in two mouse models of AKI;
2) analyse participating PDGF-dependent signalling pathways; 3) compare the course of AKI in
PDGF-D-/-- and PDGF-C-/--mice; 4) inhibit PDGFB in mice by specific aptamers following AKI and
5) depending on the results in 3) and 4) study
the outcome of AKI in mice following delivery of
recombinant PDGF-B, -C or –D or genetic overexpression. Alternatively, transgenic mice which
conditionally express one of the PDGF isoforms
behind the tubular cell specific PAX-8 promoter
will be studied in AKI.
In preliminary work we have established both AKI
models, namely the I/R (ischemia/reperfusion) and the Cis (cisplatin)-model. Upon begin of the
project in July 2011, we started to compare the
consequences of AKI (I/R-model) at different time
points following disease induction in PDGF-C defiecient mice compared to wild type littermates.
First results from day 5 tissues point to significantly reduced renal MCP1 mRNA expression,
reduced renal leukocyte infiltration and reduced
tubular damage in PDGF-C deficient mice (figure
1). The analyses of earlier and later time points
of disease as well as the consequences of AKI in
PDGF-D deficient mice are in progress.
Consequences of AKI (I/R-model) in PDGF-C deficient mice compared
to wildtype littermates on day 5. (A) MCP1 mRNA expression, (B) infiltration of F4/80 positive monocytes/macrophages/dendritic cells, (C) CD3
positive T-cells and (D) tubular damage on day 5 following disease induction. TIS: tubular injury score: evaluation for tubular flattening, presence of casts and leukocyte infiltration.
IZKF Aachen Progress Report 2011
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Inflammation and Consequences
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E6-11
Lipocalin 2 (LCN2), a central mediator in inflammatory organ
disease
Weiskirchen R. (Institute of Clinical Chemistry and Pathobiochemistry)
Borkham-Kamphorst E. (Institute of Clinical Chemistry and Pathobiochemistry)
LCN2 belongs to the lipocalin superfamily and is
involved in transport of fatty acids and iron, apoptosis induction, suppression of bacterial growth
and modulation of inflammatory responses. The
expression of LCN2 is induced under harmful
conditions including intoxication, inflammation
and other forms of cellular stress suggesting that
LCN2 is an early inflammatory biomarker. In the
present project, we aim (i) to investigate LCN2
expression in inflammatory acute and chronic
experimental liver damage, (ii) determine the he-
patic sources of LCN2 production, (iii) delineate
the mechanisms controlling LCN2 production in
vitro and in vivo, (iv) understand the molecular
functions of LCN2 in experimental models of hepatic damage, (v) test if LCN2 is a non-invasive
or prognostic biomarker for liver disease, and (vi)
finally understand the role of LCN2 in lipid metabolism (Figure 1). We have recently published
our preliminary work that was outlined in our original proposal (Borkham-Kamphorst et al. (2011)
Liver Inter 31:656-665). In the first six months of
Figure 1: Key issues of LCN2 function and regulation in inflammatory liver disease.
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IZKF Aachen Progress Report 2011
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|
Inflammation and Consequences
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E6-11
2.4.
Funding period: 01.07.2011 - 30.06.2014
Staff: ½ TV-L 13
Materials 2011: € 6,250
Investments/Equipment 2011: –
funding, we started to analyse LCN2 expression
and regulation in different models of inflammatory liver insult and performed first experiments
addressing functional aspects of this lipocalin.
We found that LCN2 is rapidly induced and sustained expressed in the course of experimental
liver injury. Immunohistochemistry and primary
liver cell isolation identified injured hepatocytes
as the main source of LCN2 production. Additionally, in vivo liver injury models show a clear LCN2
correlation with the liver damage markers serum
AST and ALT, implying the proposed diagnostic
value. We have recruited a new staff member,
Miss Anastasia Asimakopoulos, who has a strong
scientific background in biochemistry and biotechnology. She will start in our group in January
2012 and extend these studies. In summary, we
are optimistic that we are able to perform all outlined experiments and studies in the scheduled
time course and there is actually no need to make
changes on the content of our proposal.
Publications
IZKF relevant, project associated
Actually only some of our preliminary work that
was outlined in our initial proposal was published
(without IZKF acknowledgement).
1. Borkham-Kamphorst E, Zimmermann HW,
Karlmark KR, Van de Leur E, Bauer J, Tacke
F, Weiskirchen R. (2011) Lipocalin-2 (LCN2) in
experimental liver injury and human liver diseases. Z Gastroenterol 49: 88. [Abstract]
2. Borkham-Kamphorst E, Drews F, Weiskirchen
R. (2011) Induction of lipocalin-2 expression
in acute and chronic experimental liver injury
moderated by pro-inflammatory cytokines interleukin-1` through nuclear factor-gB activation. Liver Int 31:656-665. [IF 2.99]
3. Bergmann C, Weiskirchen R. (2011) It’s not all
in the cilium, but on the road to it: Genetic interaction network in polycystic kidney and liver
diseases and how trafficking and quality control matter’. J Hepatol Nov 28. [Epub ahead of
print]. [IF 9.334]
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Weiskirchen,
R. and
Büttner, R..
The impact of the LIM domain pro- DFG (SFB/
teins FHL2 and CRP2 on hepatic
TRR57, P05)
stellate cell activation and its crosstalk with TGF-` signalling pathways
in hepatic fibrogenesis
01/200912/2012
€ 423,360
Weiskirchen,
R.
Exogenous and endogenous
DFG (SFB/
modulators of PDGF/TGF-` signal- TRR57, P13)
ling in liver fibrogenesis and their
therapeutic application
01/200912/2012
€ 280,800
Tacke, F. and
Weiskirchen,
R.
FACS based cell sorting of paren- DFG (SFB/
chymal and non-parenchymal cells TRR57, Q3)
from liver and kidney
01/200912/2012
€ 963,280
IZKF Aachen Progress Report 2011
147
2.4.
Project Funding
|
Inflammation and Consequences
|
E6-11
Hoffmann,
K., Fröhlich,
H.Zenke, M.,
Wagner, W.,
Weiskirchen,
R. et al.
TGF-` signalling in murine and
human hepatocytes and hepatic
stellate
Alma-In-Silico
01/200812/2012
~ € 50,000
(group
Weiskirchen)
Becker, J. S.,
Amunts K.,
Weiskirchen,
R., Lüscher,
B., Zilles, K.
Advanced Mass Spectrometry im- DFG
aging (MSI) of metals and biomol- (Infrastructure
ecules in brain and liver - BrainMet grant)
01/201212/2015
~€
1,000,000
Promoting of young researcher
Diploma Theses
Asimakopoulos,
A.
Ongoing
RWTH Aachen,
Faculty 1
LCN2 in inflammatory liver disease
Rüland, A.
2011
RWTH Aachen,
Faculty of
Medicine
Functional relevance of the chemokine RANTES in
liver fibrosis
Lux, St.
Ongoing
RWTH Aachen,
Faculty 10
Functional analysis of CCN proteins in hepatic
fibrogenesis
Bultmann, C.
Ongoing
RWTH Aachen,
Faculty 10
Regulation and function of the LIM domain proteins
CRP2 and FHL2 in experimental models of liver
injury
Alexi, P. H.
Ongoing
RWTH Aachen,
Faculty 1
The role of TGF-` and PDGF isoforms in inflammatory liver diseases
Boaru, S.G.
Ongoing
RWTH Aachen,
Faculty 1
Expression analysis of inflammasome components
in models of inflammatory liver disease
Doctoral Theses
148
IZKF Aachen Progress Report 2011
2.4.
IZKF Aachen Progress Report 2011
149
YOUNG RESEARCHER GROUPS
Thumann
Regeneration of ocular tissue using biohybride implants
p. 153
Ludwig
Vascular Pharmacology
p. 155
JUNIOR PROJECTS
150
Sanati
p. 159
Hoss
p. 161
Kanzler
p. 162
Li
p. 163
Nazari
p. 164
Subramanian
p. 165
Clemens
p. 166
Schock
p. 168
Otten
p. 169
Ehedego
p. 171
Kraaz
p. 172
Vijayan
p. 173
DIPLOMA THESES, DOCTORAL THESES,
P O S T D O C T O R A L L E C T U R E Q U A L I F I C AT I O N
p. 176
IZKF Aachen Progress Report 2011
FUNDING
YOUNG RESEARCHER
Career Advancement from Doctoral Thesis to
Young Researcher Group Leading
In 2011, the IZKF funded two Young Researcher Groups and
12 Junior Research Projects with € 916,443. The funding programme
for Junior Research Projects ended in 2011. Fifteen diploma theses,
15 doctoral theses, and 3 postdoctoral lectures qualifications were
completed. Furthermore 18 diploma theses, 71 doctoral theses and
5 postdoctoral lectures qualifications were in progress.
IZKF Aachen Progress Report 2011
151
3.1.
Funding Young Researcher
| Young Researcher Groups
FUNDING
YOUNG RESEARCHER
Young Researcher Groups
Through the Young Researcher Groups the IZKF Aachen offers a very
attractive funding opportunity to ambitious scientists with excellent
achievements. The Researcher Groups work independently but are
attached to an institute or clinic.
The heads of the Young Researcher Groups are relieved of their clinical
obligations and can dedicate themselves to their research.
The heads of the Young Researcher Groups have outstanding scientific
qualifications, are experienced in the acquisition of third-party funding,
and are selected by the board. The External Research Advisory Board is
also involved in the selection procedure.
Two Young Researcher Groups have been funded since 2005, for
an initial funding period of three years. After a positive evaluation in
autumn 2008, the funding was extended for another three year period. The
funding for both groups will end in 2012, when four new Research Groups
will start.
152
IZKF Aachen Progress Report 2011
Funding Young Researcher
| Young Researcher Groups
| Thumann
3.1.
Funding period: 01.03.2006 - 15.10.2012
Staff: 1 TV-L 13 (Johnen S.), 1 TV-L 9
(Stickelmann C.), 1 TV-L 13 (Kazanskaya
O.), 1 TV-L 13/2 (Harmening N.),
1 TV-L1¾ (Diarra S.), 1 TV-L 13/2
(Salz A.)
Materials 2011: € 30,000
Investments/Equipment 2011: –
Regeneration of ocular tissue using biohybride implants
Thumann G. (Experimental Ophthalmology / Department of Ophthalmology)
The goals of our research were to genetically
modify RPE or iris pigment epithelial (IPE) cells
with the gene for PEF, an inhibitor of blood vessel growth, for eventual transplantation into the
subretinal space to inhibit blood vessel growth
for the life of the patient. Since classical methods for gene delivery are not appropriate for AMD
treatment because of the requirement for large
number of cells and selection in culture, we have
used the newly developed Sleeping Beauty transposon system, which is more efficient and safer
than classical methods of gene delivery. Transposons in nature are mobile DNA elements that can
transpose DNA sequences from one part of the
genome to another. In 2011 we have introduced
the PEDF gene into ARPE-19 cells and shown
that the recombinant PEDF (rPEDF) produced
by the transfected cells inhibits angiogenesis in
vitro, as evidenced by the inhibition of endothelial
cell migration (number of cell/field: 215±39 for
control vs. 97±21 for rPEDF-treated cells), sprout
formation (average sprout length: 2.80±0.15 mm
for control vs.1.35±0.14 mm for PEDF-treated
cells), and the increased percent of dead cells in
endothelial cell cultures from 14±4 to 48±3 cells.
Control and transfected IPE and RPE cells grow
and proliferate on collagen and amniotic membranes with 95% viability without evidence of genetic instability. In fact, with exception of PEDF,
which was over-expressed in transfected cells
and in IPE cells on collagen, the genes for KRT8,
ZO1, Cat-D, NF-kB, c-ABL, p53, and JNK1 did
not show any significant change in expression
whether cultured on plastic, collagen or amniotic
membranes. In preliminary experiments PEDFtransfected cells transplanted to the subretinal
space reduced the area of CNV by 48% and the
number of clinically significant lesions by 46% in
a rodent model. Using these data we have applied for an FP7-HEALTH2012.1.4-4 “Targeted
Nucleic Acid Delivery as an Innovative Therapeutic or Prophylactic Approach”.
Publications
IZKF relevant, project associated
1. Johnen S, Kazanskaya O, Armogan N, Stickelmann C, Stöcker M, Walter P, Thumann G.
Endogenic regulation of proliferation and zinc
transporters by pigment epithelial cells nonvirally transfected with PEDF. Invest Ophthalmol
Vis Sci. 2011 Jul 23; 52(8):5400-7. [IF 3.466]
2. Thumann G. Nonviral gene therapy for age-related macular degeneration. Expert Review of
Ophthalmology, 2011; 6: 81-93.
3. Johnen S, Wickert L, Meier M, Salz AK, Walter
P, Thumann G. Presence of xenogenic mouse
RNA in RPE and IPE cells cultured on mitotically inhibited 3T3 fibroblasts. Invest Ophthalmol Vis Sci. 2011; 52:2871-24. [IF 3.466]
4. Thumann G, Armogan N, Schwanz T, Gaebler
A, Vehr AK, Walter P, Mazinani B. Fulminant
postoperative endophthalmitis due to streptococcus pneumoniae. Klin Monbl Augenheilkd.
2011; 228:1108-9. [IF 0,407]
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Thumann, G.
Suitability of silk membranes for
temporary wound dressing in
ocular injury
BMWi ZIM
2009-2011
€ 168,000
IZKF Aachen Progress Report 2011
153
3.1.
Funding Young Researcher
| Young Researcher Groups
| Thumann
2010-2011
€ 88,775
Thumann, G.
Degradation of PEA fibrils in
ocular tissue
DSM
Biomedical
Thumann, G.
Investigation of attachment,
growth and effect of shear stress
of pigment epithelial cells cultured
on modified Collagen Cell Carriers
Viscofan
2011
BioEngineering
€ 28,000
Thumann, G.
Characterization of retinal degeneration models in vitro
DFG
2011-2013
TH 603/15-1
€ 281,500
Thumann, G.
Polymerfibrils from intraocular
drug delivery
DSM
Biomedical
2011-2012
€ 144,000
Thumann, G.
SMEyeSee
EU
applied:
FP7-Health2012-Innovation II
now Phase 2
Thumann, G.
Non-viral, ex-vivo gene therapy
to treat exudative AMD
AHAF
applied:
Stage 2 invited full proposal
Thumann, G.
TargetAMD
EU
€ 1,2 M
FP7Health2012-Innovation I now
Phase 2
Thumann, G.
Non-viral gene therapy for treatment of retinal degeneration
DFG
applied:
TH 603/16-1
Promoting of young researcher
Doctoral Theses
Harmening, N.
Ongoing
RWTH Aachen,
Faculty of
Medicine
MRNA based SB transfection of primary cells
Salz, A.
2011
RWTH Aachen,
Faculty of
Medicine
In vitro and in vivo studies of pigment epithelial
cells and biomaterials for subretinal transplant
development
Gaebler, A.
2011
RWTH Aachen,
Faculty of
Medicine
Biocompatibility of a collagen type I membrane in
the subretinal space
Frank, D.
2011
RWTH Aachen,
Faculty of
Medicine
Collagen foil as a carrier for cell transplantation
into the subretinal space in order to replace RPE
in AMD
Bertram, P.
Ongoing
RWTH Aachen,
Faculty of
Medicine
Characterization of the genomic stability in
non-virally transfected primary cells
Möller, T.
Ongoing
RWTH Aachen,
Faculty of
Medicine
The Anti-Angiogenic Effect of recombinant PEDF
in vitro
Awards
Novartis EYEnovative Research Award 2011
154
IZKF Aachen Progress Report 2011
Funding Young Researcher
| Young Researcher Groups
|
Ludwig
3.1.
Funding period: 01.06.2006 - 31.03.2013
Staff: 1 TV-L13 (Dreymüller D.)
1 TV-L13 (Prüßmeyer J.)
1 TV-L13 (Groth E.)
1 TV-L 9 (Esser M.)
Materials 2011: € 30,000
Vascular Pharmacology
Ludwig A. (Institute of Pharmacology and Toxicology)
Acute lung injury (ALI) is associated with increased vascular permeability and leukocyte recruitment. Several proinflammatory mediators are
released by the activity of the metalloproteinase
ADAM17, but its role in ALI is only poorly defined.
We investigated the role of ADAM10/17 in LPSinduced ALI with a particular focus on the role of
endothelial and smooth muscle cell expressed
ADAM17.
Intranasal LPS- or TNF-treatment induced all
signs of ALI in control mice including vascular
leakage, edema formation, release of proinflammatory cytokines, TNF, IL-6 and the chemokine
KC. Endotoxin treatment also increased expression of the metalloproteinase ADAM17. Treatment with GW280264X to block ADAM10/17 considerably reduced the proinflammatory response
towards LPS. The data suggest a proinflammatory role of the protease in acute lung inflammation, which was then further investigated by cell
specific knockout of the protease.
The role of ADAM17 on endothelial cells was studied by the use of Tie2-controlled adam17-knockout in endothelial cells. Cell-specific ADAM17-deficiency was confirmed by the isolation of primary
cells from knockout mice and RT-qPCR analysis
for ADAM17. LPS triggered the upregulation of
ADAM17 gene expression in the lung, which was
abrogated in Tie2-adam17-/- mice. LPS-induced
increase in vascular permeability and edema formation as well as leukocyte recruitment into the
lung tissue and the alveolar space were all markedly reduced in Tie2-adam17-/- mice. This effect
was correlated with a reduced release of TNF
and IL-6. Acute lung inflammation by intranasal
application of TNF was also dependent on endothelial ADAM17 suggesting that multiple shedding events besides endothelial TNF release are
involved in this activity. For more detailed analysis of the role of ADAM17 in the regulation of vascular permeability and transendothelial leukocyte
recruitment we used human microvascular endothelial cells (HMVEC-L). LPS simulation resulted
in increased ADAM17 expression and activity
leading to enhanced shedding of endothelial surface molecules such as the junctional adhesion
molecule JAM-A. Vascular permeability and leukocyte transmigration were then studied in transwell assays. The role of ADAM10/17 was probed
using the ADAM10/17 inhibitor GW280264, and
by lentiviral knockdown using shRNA. LPS-mediated induction of endothelial permeability as
well as IL-8-induced transmigration of neutrophils
through HMVEC-L required the activity of both
ADAM10 and ADAM17. We conclude that the
activation of ADAM17 in pulmonary endothelial
cells promotes acute pulmonary inflammation in
response to LPS.
The role of smooth muscle cell expressed
ADAM17 was addressed by the use of Taglnadam17-/- mice, lacking ADAM17 expression
in these cells. Cell-specific ADAM17-deficiency
was confirmed by the isolation of primary cells
from knockout mice and RT-qPCR analysis
for ADAM17. We next investigated the role of
SMC-expressed ADAM17 for mediating cytokine
production, vascular leakage, edema formation
and leukocyte recruitment in ALI. Compared to
wild type mice, Tagln-adam17-/- mice displayed
no increase in vascular permeability, no edema
formation, reduced release of IL-6, TNF_ and
KC and reduced neutrophil infiltration of lung in
response to LPS. Notably, Tagln-adam17-/- mice
still responded to TNF by edema formation while
cytokine production and neutrophil recruitment
were clearly reduced. Since neutrophil recruitment is strongly dependent on cytokine production, we investigated the role of ADAM17 in the
generation of proinflammatory cytokines and
growth factors by cultured tracheal SMC. SMC
from Tagln-adam17-/- mice showed reduced or
suppressed mRNA expression and release of
IL-6 and chemokines (KC, IP-10 and CXCL16).
This was confirmed by the use of human tracheal
SMC in which silencing of ADAM17 as well as
pharmacological inhibition of the EGFR pathway
decreased release of IL-6 and IL-8. We conclude
that smooth muscle expressed ADAM17 is a key
IZKF Aachen Progress Report 2011
155
3.1.
Funding Young Researcher
| Young Researcher Groups
|
player for the development of ALI by enhancing
the production and secretion of several inflammatory mediators including TNF_, IL-6, and IL-8
(KC). This function might be regulated through
the EGFR pathway.
Thus, ADAM17 holds a proinflammatory function in acute lung injury. Notably, the absence
of either endothelial or smooth muscle ADAM17
is sufficient to reduce ALI. However, in both cell
types the proinflammatory function appears to be
different. In endothelial cells ADAM17 activity is
Ludwig
required for adhesion molecule shedding, regulation of permeability and facilitation of leukocyte
transmigration. In smooth muscle cells the protease mediates shedding of EGFR ligands and
thereby promotes autocrine and paracrine cellular transactivation to produce proinflammatory
mediators that are critical for the development of
ALI. We will further investigate the role of cellspecific ADAM17 in models of chronic lung inflammation provoked by intratracheal bleomycin
or by repeated allergen challenge.
Publications
IZKF relevant, project associated
1. Dreymueller D, Pruessmeyer J, Groth E,
Ludwig A (2011) The role of ADAM-mediated
shedding in vascular biology. Eur J Cell Biol.
Dec 2. [Epub ahead of print] [IF 3,630]
2. Ludwig A, Sommer A, Uhlig S (2011) Assessment of endothelial permeability and leukocyte transmigration in human endothelial cell
monolayers. Methods Mol Biol. 763:319-32
3. Lizama C, Ludwig A, Moreno RD (2011) Etoposide induces apoptosis and upregulation
of TACE/ADAM17 and ADAM10 in an in vitro
male germ cell line model. Biochim Biophys
Acta. 1813:120-8 [IF 4,733]
4. Kim KW, Vallon-Eberhard A, Zigmond E, Farache J, Shezen E, Shakhar G, Ludwig A, Lira
SA, Jung S. (2011) In vivo structure/function
and expression analysis of the CX3C chemokine fractalkine. Blood. 118:e156-67. [IF
10,558]
5. Dreymueller D, Martin C, Kogel T, Pruessmeyer J, Hess FM, Horiuchi K Uhlig K, Ludwig A.
Lung endothelial ADAM17 regulates the acute
inflammatory response to Lipopolysaccharide,
EMBO Mol Med, accepted. [IF 8,833]
6. Weiss EM, Schmidt A, Vobis D, Garbi N, Lahl K,
Mayer CT, Sparwasser T, Ludwig A, Suri-Payer
E, Oberle N, Krammer PH (2011). Foxp3-mediated suppression of CD95L expression confers
resistance to activation-induced cell death in
regulatory T cells. J Immunol. 187:1684-91 [IF
5,757]
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Ludwig, A.
156
Role of the metalloproteinases
ADAM10 and ADAM17 in acute
lung inflammation
IZKF Aachen Progress Report 2011
DFG Lu869/5-1 03/201103/2014
€ 480,000
Funding Young Researcher
| Young Researcher Groups
|
Ludwig
3.1.
IZKF Aachen Progress Report 2011
157
Promoting of young researcher
Diploma/Master Theses
Babendreyer, A.
Ongoing
RWTH Aachen,
Biology
Assessment of leukocyte adhesion and
transmigration by impedance spectroscopy
Schumacher, J.
Ongoing
RWTH Aachen,
Biology
Role of ADAM17 in experimental lung fibrosis
Koenen, A.
Ongoing
RWTH Aachen,
Biology
Role of CXCL16 and its cleaving metalloproteinases in experimental lung allergy
Groth, E.
Ongoing
RWTH Aachen,
Biology
Regulation of ADAM17
Doctoral Theses
3.2.
Funding Young Researcher
|
Junior Projects
FUNDING
YOUNG RESEARCHER
Junior Projects
The Junior Projects Program was devised as an instrument for funding
the Research Focus Areas:
Two doctoral positions were allocated in each Research Focus Area. The
positions could be filled by two doctoral students.
The Junior Projects have been funded for a three-year funding period
and have been supervised by the coordinators of the Research Focus
Areas and/or the heads of funded projects.
The doctoral students participated in the mandatory Faculty of Medicine
MD PhD program. In addition, they could participate in specialized graduate schools in the Research Focus Areas.
Each Junior Project received an annual budget of € 7,668. The Junior
Projects ended in 2011 and the program was discontinued.
Doctoral positions will be funded exclusively in the funded projects.
158
IZKF Aachen Progress Report 2011
Funding Young Researcher
|
Junior Projects
|
Sanati
3.2.
Role of plasmacytoid dendritic cells (pDC) in atherosclerosis
Sanati M. (Institute for Molecular Cardiovascular Research)
Coronary heart disease is the most common
cause of death in the Western hemisphere. Its
main cause, atherosclerosis, is a chronic inflammation1. Central to the induction and progression
of atherosclerosis is the infiltration of the arterial
wall by immune cells which will induce sustained
inflammation2. In addition to monocytes and T
cells, DC have been shown to reside in atherosclerotic vessels in close proximity to T cells.
However, as of now it is unclear as to how these
cells are recruited to the arterial wall and what
function they might carry out3. DC are in general
specialized in the uptake, processing and presentation of antigens. Antigen-presenting cells
(APC) transport antigens in secondary lymphoid
organs to induce a specific inflammatory immune
response via attraction and activation of T cells4.
DC, however, are a heterogeneous cell population consisting of myeloid DC, lymphoid DC, as
well as plasmacytoid DC, all of which have different migratory and functional properties5, 6.
pDC are characterized by production of vast
amounts of Typ I Interferon in response to certain
antigens. Potent antigens are viral (ssRNA) and
bacterial (CpG) motives, which will be recognized
via Toll-like receptor 7 and 97. pDC progenitors
as well as their potency in inducing a direct T cell
response is disputed8. In addition, recruitment
mechanisms as well as the functional importance
of pDC in atherosclerosis are unknown. However,
pDC have been identified in the advanced human
atherosclerotic plaque and it is to be expected that
the production of interferon-alpha by pDC leads
to enhanced cytotoxic activity of T cells. This may
relate to induction of apoptosis of smooth muscle
cells and subsequent plaque instability9. Of note,
the number of circulating pDC is reduced in patients with atherosclerosis and is further negatively correlated with plaque stability10.
To assess the prevalence of pDCs in murine atherosclerotic aortas, we fed Apoe-/- mice a highfat diet. After three months aortas were excised,
enzymatically digested, stained with antibodies
to CD45, CD11c, MHCII, PDCA, and 440c and
subsequently analyzed by FACS. Using such
approach, we found that about 0.75% of CD45+
cells were pDCs. To further study recruitment of
these cells we will use intravital fluorescence microscopy and 2-photon microscopy. In addition,
we will use FACS and real time PCR to analyse
chemokine receptor expression on pDCs. Subsequently, we will analyse the recruitment of pDCs
in mice lacking specific chemokine receptors.
The importance of pDCs during onset and progression of atherosclerosis is evaluated in mice
depleted of pDCs or in mice where pDCs are
activated by injection of CpG. Preliminary data
suggest that depletion of pDC in mice that had
been on diet for four weeks have a lower atherosclerosis burden when compared to control mice.
In contrast, pDC activation by application of CpG
increases the degree of atherosclerosis suggesting that pDCs do exert pro-atherogenic effects.
In further experiments we will study the stage
specific effect of pDCs.Mechanistically, pDCs
may be activated by proatherogenic factors such
as oxidatively-modified LDL. In deed we found
that pDCs effectively take up fluorescent oxLDL.
However, this interaction does not result in induction of IFN-alpha or costimulatory molecule
expression. Nevertheless, in an OT-II OVA II antigen-specific T cell proliferation assay we found
that pDCs treated with oxLDL/OVA II resulted in
enhanced T cell proliferation in comparison to
pDCs loaded with OVA II only. In these assays,
however, the exposure of pDCs to oxLDL/OVA
II does not affect cytokine secretion, suggesting
that oxLDL may enhance OVA II uptake leading
to increased T cell proliferation. In conclusion, it
seems that oxLDL per se may not activate pDCs
to enhance IFN-alpha secretion. However, other
factors relevant to atherosclerosis such as neutrophil-derived granule proteins (LL37/CRAMP)
or autoimmune complexes may promote pDC activation. Further experiments shall shed light on
the importance of these factors to pDC activation
in atherosclerosis.
IZKF Aachen Progress Report 2011
159
3.2.
Funding Young Researcher
|
Junior Projects
|
Sanati
Promoting of young researcher
Doctoral Theses
Sanati, M.
160
IZKF Aachen Progress Report 2011
Ongoing
RWTH Aachen
Role of plasmacytoid dendritic cells (pDC) in
atherosclerosis
Funding Young Researcher
|
Junior Projects
|
Hoss
3.2.
IZKF Aachen Progress Report 2011
161
Cardiomyogenic Differentiation of gPS Cells on the
Biomaterial Resomer® LR704
Hoss, M. (Institute for Biomedical Engineering, Cell Biology;
Intitute for Pathology, Stem Cells and Tissue Engineering)
Stem cells with unlimited differentiation potential, like the recently described germline-derived
pluripotent stem (gPS) cells [Ko et al., Cell Stem
Cell, 2009], are an appealing cell source for tissue engineering. Pluripotency of gPS cells has
been proved by expression of the pluripotency
factors Oct4, Nanog and Sox2.
Biomaterials can inhibit, support or induce proliferation and differentiation of stem cells. Therefore, we intend to identify polymers which maintain self-renewal and differentiation potential of
gPS cells.
A panel of degradable and non-degradable polymers of an established biomaterial bank is used
in this study [Neuss et al., Biomaterials, 2008].
Identification of cytocompatible gPS cell/biomaterial-combinations requires analyses of several
parameters including morphology, vitality, cytotoxicity, apoptosis, proliferation and differentia-
tion potential. Flow cytometry analysis, viability
assay and proliferation assay have shown that
gPS cells efficiently adhere to and are viable on
synthetic polymers, like PTFE (polytetrafluorethylene) and PVDF (poly(vinylidene fluoride) and
on gelatin-coated TCPS (tissue culture polystyrene). Furthermore, gelatin-coated TCPS and
LR704 could be described as an alternative for
feeder-free expansion of gPS cells.
Differentiation experiments with embryoid bodies
showed beating areas – indicating a cardiomyogenic differentiation- 2 days earlier on LR704
than on the other materials. Cardiomyogenic
differentiation of gPS cells on LR704 has been
proven by documentation of beating areas, electrophysiological measurements, expression of
Connexin 43, sarcomeric _-Actinin on RNA and
protein level and a microarray assay.
Publications
IZKF relevant, project associated
1. Hoss M (2011) Integrin _4 impacts on differential adhesion of preadipocytes and stem cells
on synthetic polymers. Journal of Tissue Engi-
neering and Regenerative Medicine. 2011 Oct
4. [Epub ahead of print]
Impact factor: 3,534
3.2.
Funding Young Researcher
|
Junior Projects
|
Kanzler
Role of MIF in eEPC transplantation in murine and porcine
models of myocardial infarction
Isabella Kanzler (Institute of Biochemistry and Molecular Cell Biology)
Using endothelial progenitor cells (EPCs) in cardiovascular cell therapy is an auspicious tool for
repairing and regenerating cardiovascular cells in
diseased patients. Embryonic endothelial progenitor cells (eEPCs) are characterized by favorable
growth behavior and can be used in syngenic
and xenogenic transplantation after clonal in vitro
expansion. It has been shown, that eEPCs carry
a battery of pro-angiogenic factors with them
as cargo. Furthermore, angiogenic factors like
VEGF-B and the chemokine-like cytokine macrophage migration inhibitory factor (MIF), which
acts protectively after myocardial infarction, are
expressed and secreted by eEPCs. Recently, it
was shown that MIF binds to the chemokine receptors CXCR2 and CXCR4 and that these two
receptors play a crucial role in EPC recruitment.
This project has investigated the angiogenic potential of eEPCs and MIF in murine models in
vivo as well as in vitro, comparing the specific
potential of MIF with that of other EPC-borne angiogenic factors such as VEGF and the alterna-
tive CXCR2/4 ligands CXCL1 and CXCL12. Additionally, the role of the CXCR4 axis in models of
myocardial infarction was investigated.
A key finding was that EPC-derived MIF has a pivotal angiogenic role following hypoxic challenge,
including EPC recruitment, EPC differentiation
and subsequent tube and vessel formation. For
example, MIF was the only angiogenic factor able
to induce a differentiation towards an endothelial
and SMCs phenotype, whereas co-loading of
plugs with eEPCs and angiogenic proteins led to
enhanced tube formation by CXCL12 but not by
MIF. These findings have important implications
for devising pro-angiogenic therapies in the treatment of CVD. Another finding of this project was
that CXCR4 plays a crucial role in endo¬¬genous
remodeling processes after myocardial infarction, contributing to inflamma¬tory/progenitor cell
recruitment and neovascularization, whereas its
deficiency limits infarct size and causes adaptation to hypoxic stress.
Publications
IZKF relevant, project associated
1. Kanzler I, Liehn EA, Koenen RR, Weber
C (2011) Anti-inflammatory therapeutic approaches to reduce acute atherosclerotic complications. Curr Pharm Biotechnol 13:37-45 [IF
3.455]
2. Liehn EA, Tuchscheerer N, Kanzler I, Drechsler
M, Fraemohs L, Schuh A, Koenen RR, Zander
S, Soehnlein O, Hristov M, Grigorescu G, Urs
AO, Leabu M, Bucur I, Merx MW, Zernecke
A, Ehling J, Gremse F, Lammers T, Kiessling
F, Bernhagen J, Schober A, Weber C (2011)
Double-edged role of the CXCL12/CXCR4
axis in experimental myocardial infarction. J
Am Coll Cardiol 58:2415-2423 [IF 14.292]
Promoting of young researcher
Doctoral Theses
Kanzler, I.
162
IZKF Aachen Progress Report 2011
Ongoing
RWTH Aachen
Faculty 1,
Biology
Therapeutic potential of MIF in angiogenesis: novel
insights and comparison with established angiogenic factors
Funding Young Researcher
|
Junior Projects
|
Li
3.2.
IZKF Aachen Progress Report 2011
163
The molecular effects of biofunctional pro-EPC mini stents
Li X. (Institute for Molecular Cardiovascular Research)
Accelerated re-endothelialization of implanted
stents may reduce the development of neointima
formation and thus may prevent in-stent restenosis. In addition, in stent thrombosis may be limited
by enhanced endothelial coverage of the stents.
RGD coated stents are believed to assist in the
targeted recruitment of circulating EPCs and
may provide a promising alternative to the currently used compounds. We immobilized RGD
on starPEG coated stents in the recruitment of
EPCs to prevent in-stent restenosis in our newly
developed murine stent model.
Using in vitro assays we demonstrated the immobilization and biological effect of the compounds by studying the adhesion of endothelial
progenitor cells (EPCs) and human umbilical vein
endothelial cells (HUVECs). In contrast, smooth
muscle cells did not adhere to the functionalized
stent surface. Further studies are needed to establish the role of this stent coating in vivo. However, in the murine stent model it is difficult to get
enough sections for immunohistochemistry and
the staining is also much more difficult due to the
embedding of the tissue.
In conclusion, biofunctionalization of stents is a
promising approach in vitro to enhance the endothelial coverage. The full re-endtohelialization
of the mini stent in vivo is however difficult to
confirm.
Promoting of young researcher
Doctoral Theses
Li, X.
Ongoing
RWTH Aachen
The molecular effects of biofunctional pro-EPC
mini stents
3.2.
Funding Young Researcher
|
Junior Projects
|
Nazari
EPC subpopulations and endothelial function after stent
implantation and myocardial infarction
Nazari-Jahantigh M. (Institute for Molecular Cardiovascular Research)
Peripheral blood contains CD34+ cells that include endothelial progenitor cells (EPCs) which
can differentiate into mature endothelial cells.
In addition CD14+ cells include angiogenic cells
which are characterized by the additional expression of CD16 and the receptor for angiopoetin,
Tie2. An optimized flow cytometry protocol was
established to quantify human CD34+ EPCs and
angiogenic monocytes subsets. Using this protocol, the circulating EPCs and monocytes subsets
in patients were correlated with the cardiovascular risk profile and with the extend of coronary
artery disease.
We recruited 80 patients with stable coronary artery disease and quantified angiogenic Tie2CD14++CD16+ monocytes and
CD34+VEGFR2+CD45- EPCs. Furthermore
other monocytes subsets such as CD14++CD16, CD14++CD16+, and CD14lowCD16+, were
measured in the peripheral blood. We are currently correlating the different cell populations
with the presence of cardiovascular risk factors.
Additional group of patients after myocardial in-
farction or coronary stent implantations is now
being evaluated. We also started to review the
course of the coronary artery disease in terms of
major clinical events and try to establish the predictive value of the circulating cell populations.
Up to now, the analyzed numbers of patients
indicate that CD14lowCD16+ monocytes were mobilized into the circulation after an initial expansion of CD14high monocytes in patients with acute
myocardial infarction. Furthermore, EPCs and
angiogenic monocytes appear to be decreased in
patients with advanced coronary artery disease.
In contrast, inflammatory monocytes tend to be
elevated in patients with coronary artery disease.
To functionally correlate the number of peripheral
CD14lowCD16+ monocytes in contrast to CD14high
monocytes and classical CD34+VEGFR2+ EPCs
with the endothelial function as determined by
flow-mediated dilatation of arteries and the intima-medial thickness of the carotid artery with
ultrasonography in patients with coronary heart
disease.
Promoting of young researcher
Doctoral Theses
NazariJahantigh, M.
164
IZKF Aachen Progress Report 2011
Ongoing
RWTH Aachen
EPCs and Monocytesubsets in coronary artery
disease
Funding Young Researcher
|
Junior Projects
|
Subramanian
3.2.
Mechanisms of re-endothelialisation after vascular injury
Pallavi Subramanian (Institute for Molecular Cardiovascular Research)
Vascular injury after stent implantation results in
endothelial denudation, which promotes neointimal growth and restenosis in patients. To prevent
the formation of excessive neointima, enhanced
endothelial recovery may be a promising therapeutic approach. We study the molecular mechanisms of chemokines and chemokine receptors in
the recruitment of circulating endothelial progenitor cells (EPCs) to injured arteries.
We found that sorted and fluorescently labelled
CD14lowCD16+ and CD14high monocytes do not
enhance the endothelial recovery following injury.
In contrast, murine Gr-1low and Gr-1high monocytes are partly able to incorporate into injured
endothelial monolayers which mechanistically
depend on CXCR2 and CX3CR1 expression.
However, capillary sprouting of monocytes subpopulations has not been found using Matrigel
assays.
In conclusion, functional angiogenic capacity of
monocytes subpopulations differs between human and murine monocytes. This angiogenic
activity, however, is primarily observed in injured
endothelial monolayers.
Promoting of young researcher
Doctoral Theses
Subramanian, P.
Ongoing
RWTH Aachen
Mechanisms of re-endothelialisation after
vascular injury
IZKF Aachen Progress Report 2011
165
3.2.
Funding Young Researcher
|
Junior Projects
|
Clemens
An fMRI investigation on how attentional networks can be
examined with clinically relevant assessment paradigms in
healthy participants
Clemens, B. (Neurological Clinic, Section Neuropsychology)
The goal of the present project is to find out
whether attention functions, as employed in diagnostic test and therapeutic training paradigms
(CogniPlus; WAF; Sturm, 2007), share the same
neurofunctional architecture. We plan to study differences and similarities in the neural representation of 3 different attention functions, each examined with two different kinds of paradigms (test vs.
training). Both test and training paradigms were
derived from and resembled the original attention
paradigms of two large test batteries (CogniPlus;
WAF; Sturm, 2007), which are normally used for
work with stroke patients suffering from attention
deficits. Functional magnetic resonance imaging
(fMRI) is employed to evaluate changes in brain
activity associated with alertness, focused and
divided attention in healthy participants (20yrs 40yrs). The functional neuroanatomy of alertness,
focused and divided attention will be compared
between different groups of participants, whereas
the test- and training networks corresponding to
the same aspect of attention (e.g. alertness test
vs. alertness training) will be compared within the
same group of participants. During 2011, interesting results concerning the functional neuroanatomy of intrinsic alertness, as studied with diagnos-
tic test and therapeutic training paradigms (WAF
& CogniPlus) have been analyzed and published
(Clemens et al., 2011). Figure 1 visualizes one of
the major conclusions of this publication, showing highly different activation patterns during the
beginning and end of a task block of intrinsic
alertness. The published results further highlight
the potential explanatory value of using more
clinically relevant assessment paradigms within
the field of cognitive neuroscience. During 2011,
we submitted an additional second manuscript to
an international, peer-reviewed, scientific journal.
This manuscript provides a comprehensive comparison of the neural correlates of alertness and
focused attention, as examined with two different
assessment paradigms. Overall, the findings of
the present project corroborate the hypothesis
postulating a common neuronal substrate for
basic attention functions, even if they were experimentally assessed using highly different
paradigms. We suggest that the postulated common neural substrate should be independent of
the operationalisation used to activate it, and it
should be reliably accessible in different experiments using different assessment paradigms.
Publications
IZKF relevant, project associated
1. Clemens B, Zvyagintsev M, Sack A, Heinecke
A, Willmes K, Sturm W (2011) Revealing the
Functional Neuroanatomy of Intrinsic Alert-
ness Using fMRI: Methodological Peculiarities.
PLoS ONE 6(9): e25453. doi:10.1371/journal.
pone.0025453 [IF 4.411]
Promoting of young researcher
Doctoral Theses
Clemens, B.
166
IZKF Aachen Progress Report 2011
Ongoing
RWTH Aachen,
Examining different attention functions using
Faculty of Medicine functional magnetic resonance imaging
Funding Young Researcher
|
Junior Projects
|
Clemens
3.2.
Figure 1: fMRI results showing activity at the beginning and the end of the intrinsic alertness blocks
Figure 1 – Legend: Whole-brain results of the fMRI analysis (RFX-GLM; n = 16). Clusters of activation result from the contrast
Block-Beginning > Fixation in the upper part of the Figure, and from the contrast Block-Ending > Fixation in the lower part of
the Figure. For visualization, results were projected onto the optimized 3D surface reconstruction which represents the average
brain of all participants. All activations were thresholded at q(FDR) , 0.05 (t = 3.71). While the beginning of the intrinsic alertness task is associated with less activation (relative to baseline), including alertness-related areas such as the right BA 40, the
ending of the intrinsic alertness task is associated with widespread activations, including the fronto-parietal intrinsic alertness
network. (A = anterior; BA = Brodmann area; P = posterior).
IZKF Aachen Progress Report 2011
167
3.2.
Funding Young Researcher
|
Junior Projects
|
Schock
Lateralized attention in depression and mood-dependent
modulation of spatial attention
Schock L. (Department of Psychiatry, Psychotherapy and Psychosomatics)
Abnormalities in visuospatial attention in depressive disorder were predicted by alertness and
sad mood on a trend-level (Schock et al., 2011).
The interaction of emotion processing and cognitive function in the right hemisphere was reflected
in a processing bias in favour of right-ear stimuli
in dichotic listening (Schock et al., PLoS ONE,
accepted). Deviant acoustic stimuli may serve as
crossmodal spatial cues, reflecting early attention
modulation.
A dichotic oddball sequence was administered
in healthy participants to elicit crossmodal cueing effects of the acoustic deviants influencing
processing of visuospatial stimuli (see Fig.1a).
Deviant acoustic stimuli were expected to elicit
hemodynamic mismatch responses in the audi-
tory cortex. The spatial (in)congruency effect may
be differentially represented for visual stimuli with
positive and negative valence.
The effect of spatial (in)congruency yielded
salience-related responses (see Fig.1b) with
positive valence (Fig.1c) yielding left-lateralized
medial frontal responses as opposed to negative valence (Fig.1d). Target analysis revealed
stronger responses to incongruent constellations
at both auditory cortices. In conclusion, automatic
mismatch responses seem to comprise early attention components, reflected in salience effects
triggered by spatial (in)congruency. Moreover, laterality effects of (in)congruency are documented
(Schock et al., in preparation).
Publications
IZKF relevant, project associated
1. Schock L, Schwenzer M, Sturm W, Mathiak K (2011) Alertness and visuospatial attention in clinical
depression. BMC Psychiatry 11:78 [IF 2,89]
Promoting of young researcher
Doctoral Theses
Schock, L.
168
IZKF Aachen Progress Report 2011
2011
RWTH Aachen,
Medical School
Alertness and visuospatial attention in clinical
depression
Funding Young Researcher
|
Junior Projects
|
Otten
3.2.
Function and regulation of the NAD+-dependent deacetylase
SIRT2 in neurodegeneration
Daniela Otten (Department of Biochemistry and Molecular Biology)
Neurodegenerative processes are associated
with the accumulation of aggregates of misfolded
proteins, which is closely linked to cellular stress.
Inadequate processing of protein aggregates,
e.g. by the autophagosomal or by the ubiquitinproteasomal system, is critical for the phenotype because these aggregates affect normal
physiological protein turnover and intracellular
transport processes. Both are regulated by posttranslational modifications including acetylation.
As described in a study of Jeong et al. (Cell 137,
60, 2009) acetylation of an aggregation prone
huntingtin fragment stimulates its degradation in
autophagosomes. Further data depicted the ability of acetylated FoxO1 to stimulate autophagy
after dissociation from SIRT2 (Zhao et al., Nat
Cell Biol, 12, 665, 2010).
In our experiments SIRT2 knockdown led to beneficial effects in cell culture models of Huntington’s disease. In absence of the deacetylase we
observed less accumulation of mutant proteins
associated by a lower apoptosis rate. Importantly
the cytotoxic effects of the huntingtin fragment
were due to the formation of aggregates and not
the protein itself. Moreover we could establish
that SIRT2 influences autophagic degradation as
measured by p62 turnover. Initial experiments denote the relevance of the two SIRT2 phosphorylation sites, Ser-331 and Ser-335, which will now
be analysed in detail.
a)
d)
b)
e)
c)
f)
Figure 1: SIRT2 alleviates huntingtin-mediated toxicity by decreasing the number of aggregates in cells transiently expressing
GFP-Htt-Q103 plasmid. a) Viability of HEK293 as assessed by morphology. b) Apoptosis rate of SH-SY5Y neuroblastoma
measured by Parp1 cleavage. c) Immunofluorescence staining of an apoptotic SH-SY5Y cell. d) Western Blot analysis of total
cleaved-Parp in HEK293 cells. e) Quantification of aggregate containing HEK293 cells under SIRT2 knockdown. f) Viability of
HEK293 under SIRT2 knockdown.
IZKF Aachen Progress Report 2011
169
3.2.
Funding Young Researcher
|
Junior Projects
|
Otten
Promoting of young researcher
Doctoral Theses
Otten, D.
170
IZKF Aachen Progress Report 2011
Ongoing
RWTH Aachen, Function of SIRT2 in neurodegenerative disorders
Institute of
Biochemistry and
Molecular Biology
Funding Young Researcher
|
Junior Projects
|
Ehedego
3.2.
IZKF Aachen Progress Report 2011
171
Relevance of cell cycle regulators for the progression of
NEMO¨hepa induced acute and chronic liver disease
Ehedego Haksier (Department of Medicine III)
Hepatocyte specific NEMO (Nemo¨hepa) knockout
mice develop chronic hepatitis leading to liver fibrosis and carcinogenesis. This phenotype is associated with an overexpression of the cell cycle
inhibitor p21. To study the relevance of the p21
overexpression for the progression of Nemo¨hepadependent chronic liver-injury, we generated
Nemo¨hepa p21-/- mice. Our study shows that
deletion of p21 in Nemo¨hepa mice exacerbates
basal proliferation, apoptosis and hepatocarcinogenesis. p21 therefore has a protective effect in
Nemo-deficient livers and inhibits hepatitis-dependent disease progression.
In a second part of the project we analyzed the
role of the two cell cycle regulators Cyclin E1 and
Cyclin E2 for the progression of the Nemo¨hepadependent chronic liver-injury. We found that
in NEMO¨hepa E1-/- mice, the phenotype was
ameliorated compared to NEMO¨hepa single and
NEMO¨hepa E2-/- double knockout mice. The
NEMO¨hepa E1-/- mice showed less infiltration and
less fibrosis progression already at young age (8,
13 week). Additional aging experiments revealed
less tumors in NEMO¨hepa E1-/- mice compared to
NEMO¨hepa and NEMO¨hepa E2-/- littermates.
Publications
IZKF relevant, project associated
1. Ehedego H, Boekschoten MV, Muller M,
Gassler N, Liedtke C, Trautwein C. (2011)
LOSS OF P21 INCREASES TUMORIGEN-
ESIS AND SUSCEPTIBILITY TO LPS-INDUCED LIVER INJURY IN NEMO(¨HEPA)
ANIMALS. Hepatology 54:716A-716A.
Promoting of young researcher
Doctoral Theses
Ehedego, H.
Ongoing
RWTH Aachen,
Faculty 1
Relevance of cell cycle regulators for the
progression of NEMO¨hepa induced acute and
chronic liver disease
3.2.
Funding Young Researcher
|
Junior Projects
|
Kraaz
Mechanisms of inflammatory podocyte damage
Kraaz, Veronika (Internal Medicine II)
Specialized renal epithelial cells belonging to the
glomerular filtration barrier (the podocytes) have
only a limited capacity to adapt to renal damage.
Both the attempt of cell divison and necrosis/
apoptosis participate in podocytopenia, which
is assumed to be the main cause of glomerulosclerosis. By podocyte specific deletion of either
Caspase 8 or NEMO (IKK-a) we here follow the
hypothesis that podocytic Caspase-8 has a proapoptotic role in inflammatory renal disease,
whereas podocytic NEMO is assumed to function
anti-apoptotic. Podocyte-specific knockout (ko)
mice for either Caspase-8 or NEMO were generated, and both turned out to exhibit no spontaneous renal phenotype at 15, 20 and 30 weeks of
age. To investigate the consequences of inflammatory podocyte damage in NEMO ko mice antiglomerular basement membrane (GBM)-nephritis
was induced in n=16 Cre--mice (WT littermates)
and n=14 Cre+-mice (podoc. specif. NEMO ko).
Renal function was assesssed on days 7 and 14;
renal tissue was analyzed following sacrifice of the
animals on day 14 following disease induction. As
a result, podocytic NEMO loss led to a significant
reduction of proteinuria and albuminuria on day
7, whereas no significant differences between ko
and WT littermates could be detected on day 14.
Renal tissues on day 14 revealed no changes in
podocyte numbers and glomerular fibrinogen deposition. However the NEMO ko animals showed
significantly increased numbers of CD3+ T-cells in
172
IZKF Aachen Progress Report 2011
the glomeruli (Fig. 1A) and renal interstitium (Fig.
1B). In contrast, the number of renal infiltrating
neutrophils and monocytes/macrophages were
not changed upon podocytic NEMO deletion. Importantly, the glomerular podocin expression was
significantly increased on day 14 in the NEMO
ko, the GBM thickness reduced, and the number
of podocytic foot processes increased. In addition
to the in vivo studies, we blocked NEMO in vitro
in cultured conditionally immortalized podocytes
by a specific siRNA and confirmed the increased
expression of podocin upon NEMO inhibition. In
summary, podocytic NEMO ko in an inflammatory
renal disease model surprisingly improves renal
function at an early stage of the disease, which
is obviously mediated by protective effects on
podocyte function.
Anti-GBM-nephritis was also induced in the
Caspase-8 mouse line in n=22 Cre--mice (WT
littermates) and n=23 Cre+-mice (podoc. specif.
Caspase-8 ko). Analyses in these mice are still
ongoing, however, initial data show increased
proteinuria on day 7, an increase of the GBM
thickness, and a decrease of the number of foot
processes on day 14. Unexpectedly therefore,
podocyte-specific Caspase-8 seems to have a
protective effect in inflammatory renal disease.
Note: Due to a prolonged disease of the junior
project leader this project could not be finished in
the appropriate time.
Funding Young Researcher
|
Junior Projects
|
Vijayan
3.2.
IZKF Aachen Progress Report 2011
173
Neutrophil mechanisms aiding atherosclerosis
Vijayan S. (Institute for Molecular Cardiovascular Research)
This study strives to understand the role of plasmacytoid dendritic cells (pDC) and polymorphonuclear neutrophilic leukocytes (PMN) in atherosclerosis.
Coronary heart disease is the most common
cause of death in the western hemisphere. Its
main cause, atherosclerosis, is a chronic inflammation. Central to the induction and progression
of atherosclerosis is the infiltration of the arterial
wall by immune cells, which will induce sustained
inflammation. Monocytes/macrophages are of
paramount importance, PMN have recently also
been implicated in lesion formation. However, as
of now it is unclear as to how these cells are recruited to the arterial wall and what function they
might carry out.
Dendritic cells (DCs) are in general specialized in
the uptake, processing and presentation of antigens. DCs are very heterogenous group of antigen presenting cells consisting of myeloid DCs,
lymphoid DCs, as well as plasmacytoid DCs, all
of which have different migratory and functional
properties and their role in atherosclerotic lesion
formation is not clear. Very less is known about
pDCs in this context.
Thus, we wanted to unravel the role of pDC in
atherosclerosis. Besides the detection of murine
pDCs in atherosclerotic lesions, it could be further demonstrated, that specific pDC activation
significantly aggravates atherosclerotic lesion
formation, while depletion of pDCs decreases
early plaque development. Mechanistically, pDCs
may be activated by proatherogenic factors such
as oxidatively-modified LDL (oxLDL). Indeed
we found that pDCs effectively take up fluorescent oxLDL. However, this interaction does not
result in induction of IFN-alpha or costimulatory
molecule expression. We investigated the role of
chronic myelogenous leukemia (CML)-like phenotype with expanded PMN but reduced frequencies of monocytes in bone marrow and peripheral
blood in atherosclerosis-prone apolipoprotein
E-deficient (Apoe-/-) mice reconstituted with Irf8-/bone marrow was associated with an increased
lesional accumulation of PMN, apoptotic cells, a
more pro-inflammatory plaque phenotype, and
exacerbated atherosclerotic lesion formation in
comparison to Irf8+/+ bone marrow-recipient Apoe-/mice. Although accumulating in equal numbers
at sites of inflammation and plaque growth, Irf8-/macrophages were defective in phagocytosis of
apoptotic cells and lipids as well as cytokine production, contrasting unaffected reactive oxygen
species formation, and discharge of PMN granule components by Irf8-/- compared to IRF8+/+
PMN. Depletion of PMN in atherosclerotic mice
reconstituted with Irf8-/- bone marrow abrogated
increased lesion formation. These data indicate
that the expansion of functionally intact PMN in ill
alliance with impaired macrophage functions critically contribute to atherosclerosis and imply that
long-standing CML-syndroms may associate with
enhanced atherosclerosis.
Also, granule proteins released by neutrophils promote recruitment and activation of DCs, resulting
in increasing the innate and adaptive response.
In addition various complement receptors and
Fc-receprtors are involved in maturation of DCs
and influence antigen presentation. Complement
receptors are expressed on immune (neutrophils,
macrophages and immature DCs) cells and in
tissues. Neutrophil recruitment is dependent on
C5a receptor and FcaRIIA mediated phagocytosis and oxidative burst in vitro. Neutrophil function reduces with reduction of C5aR, complement
activation leads to generation of the anaphylatoxins C3a and C5a as a result of Inflammation.
To assess the characteristric influence of complement receptors and PMN on atherosclerosis,
the human plaque tissues are elucidated for the
stage dependent expression for C5a receptors.
In addition the effect of oxLDL was studied on
PMN with respect to atherosclerosis.
However, other factors relevant to atherosclerosis such as neutrophil-derived granule proteins
(LL37/CRAMP) or autoimmune complexes may
promote pDC activation which needs to be examined.
3.2.
Funding Young Researcher
|
Junior Projects
|
Vijayan
Publications
IZKF relevant, project associated
1. Döring, Y.*, Soehnlein, O.*, Drechsler, M., Meiler, S., Shagdarsuren, E., Hartwig, H., Hieronymus, T., Hristov, M., Koenen, R.R., Zenke, M.,
Weber, C., and Zernecke, A., Chronic myelogenous leukemia-like disease due to hematopoietic IRF8-deficiency fuels atherosclerosis in
mice. Circulation Research, 2011 (in revision).
2. Soehnlein O, Wantha S, Simsekyilmaz S,
Döring Y, Megens RT, Mause SF, Drechsler
M, Smeets R, Weinandy S, Schreiber F, Gries
T, Jockenhoevel S, Möller M, Vijayan S, van
Zandvoort MA, Agerberth B, Pham CT, Gallo
RL, Hackeng TM, Liehn EA, Zernecke A, Klee
D, Weber C. (2011), „Neutrophil-Derived Cathelicidin Protects from Neointimal Hyperplasia“, Sci Transl Med 3, 103ra98, Impact factor:
3.292
3. Vijayan S, Grommes J, Soehnlein O, Lutgens
E, Weber C, Schober A, Shagdarsuren E, Expressions of both complement C5a receptors
(C5aR and C5L2) in different stages of human
atherosclerotic plaques, ATVB, 2012 (manuscript under preparation)
Promoting of young researcher
Doctoral Theses
Vijayan, S.
174
IZKF Aachen Progress Report 2011
Ongoing
RWTH Aachen,
Faculty 1
Neutrophil mechanisms aiding atherosclerosis
3.2.
IZKF Aachen Progress Report 2011
175
3.4.
Funding Young Researcher
|
Diploma theses, Doctoral theses, Postdoctoral lectures
FUNDING
YOUNG RESEARCHER
Diploma theses, Doctoral theses,
Postdoctoral lecture qualification
Diploma Theses
176
T6
Peusquens,
J.
Ongoing University Bonn
Evaluation of the fate of endothelial cells
on hydrogels for the vascular grafts and
BioStent cell lining
T8
Lenz, M.
2011
RWTH Aachen,
Faculty of Electrical
Engineering
Ultra-high resolution three-dimensional
optical coherence tomography for the
analysis of dynamic processes
T9
Duffy, M.P.
2011
RWTH Aachen,
Faculty 1
Physiological bone modeling and remodeling simulation and the development
of an osteocyte computational communication network
T9
Houben, A.
2011
RWTH Aachen,
Biology
The expression of VEGF in chondrocytes
due to mechanical forces
K1-4
Klasen, C.
2011
RWTH Aachen,
Faculty 1
Role of MIF and its receptors in B l
ymphocytes
K1-4
Paten, C.
2011
FH Aachen/Jülich
Secretion of the cytokine macrophage
migration inhibitory factor (MIF) following
inflammatory stimulation
K1-4
Hennes, T.
2011
RWTH Aachen,
Faculty 1
Structure-activity-relationships of the MIF/
CXCR axis through application of so-called
MIF-ELR und MIF N-loop mutants
N1-1
Buchkremer, Ongoing RWTH Aachen,
S.
Faculty 1
Identification of new factors from the SIL1
interactome
N1-2
Hymes, H.
2011
RWTH Aachen,
Faculty 1
The influence of amyloid-beta protein on
the expression of cytochrome c oxidase
isoforms
N1-3
Schall, N.
2011
RWTH Aachen,
Institute of Biochemistry and
Molecular Biology
Regulation of the p35/CDK5 kinase
complex and its role in controlling SIRT2
in melanoma
N2-1
Zweerings,
J.
Ongoing Maastricht,
Faculty of
Psychology
Neuroendocrine stress-responses to social
rejection in a sample of children with early
separation experiences
N2-2
Kelke, J.
Ongoing RWTH Aachen,
L&F Logopädie
The effect of getsures on lexical retrieval in
aphasia
IZKF Aachen Progress Report 2011
Funding Young Researcher
|
Diploma theses, Doctoral theses, Postdoctoral lectures
N2-2
Haber, E.-M. Ongoing RWTH Aachen,
L&F Logopädie
Naming in aphasia and sound:
Development of a naming test with the
help of sounds
N2-2
Bartsch, A.
Thinking and Speaking: Investigating the correlation of linguistic and other cognitive mental
processes in aphasia: a single case study
N2-2
Schlapka, M. Ongoing Friedrich-WilhelmsUniversity Bonn
Phonetic skills in a single case of early
cochlea implantation: a longitudinal study
N2-2
Byell, L.
Schultze, J.
Ongoing Faculteit Logopedie,
Hogeschool Zuyd,
Heerlen
Reading and writing skills in hearing
Children of deaf adults (CODAs)
N2-2
Wendland,
M.-K.
Ongoing RWTH Aachen,
L&F Logopädie
I Can‘t find the right word - in sentences:
a single case study on therapy of anomia
in complex contexts in childhood aphasia
N2-2
Eidt, B.
Ongoing RWTH Aachen,
L&F Logopädie
Gestures in aphasic communication
N2-2
Marré, H.
Ongoing RWTH Aachen,
L&F Logopädie
Neurovitals
N3
Oetken, S.
2011
RWTH Aachen,
Department of
Psychiatry,
Psychotherapy and
Psychosomatics
Shared intentions and gestures:
the neurodevelopmental effects in
mentalizing network
N3
Kintzel, F.
2011
RWTH Aachen,
Department of
Psychiatry,
Psychotherapy and
Psychosomatics
The influence of semantic categories on
single word production in schizophrenia and
healthy controls
N3
Fetz, K.
2011
RWTH Aachen,
Department of
Psychiatry,
Psychotherapy and
Psychosomatics
Emotional verbal fluency in psychiatric
patients and healthy controls
N4-1
Jamnicki, A.
Ongoing University of
Maastricht
N4-5
Schlüter, T.
2011
Maastricht University, The Impact of Dopamine on Aggression:
Faculty of
An [18F]DOPA PET Study
Psychology and
Neuroscience
RWTH Aachen,
Faculty of Medicine
N5-2
Schall, N.
2011
RWTH Aachen,
Institute of
Biochemistry and
Molecular Biology
Ongoing University Cologne,
Linguistik
3.4.
Impact of aggressive behaviour in boys on
inhibition in an emotional GoNogo task
Regulation of the p35/CDK5 kinase
complex and its role in controlling SIRT2
in melanoma
IZKF Aachen Progress Report 2011
177
3.4.
Funding Young Researcher
|
Diploma theses, Doctoral theses, Postdoctoral lectures
N5-3
Buchkremer, Ongoing RWTH Aachen,
S.
Faculty of Medicine
Identification of new factors from the SIL1
interactome
E6-1
Dohmen, M. 2011
RWTH Aachen,
Medical School
Investigation of the TLR4-induced
autophagy pathway downstream of p38:
Connection to cell cycle
E6-2
Levikova, M. 2011
RWTH Aachen,
Faculty 1
Mechanism of endotoxin tolerance in
mast cells
E6-2
Kläner, O.
Ongoing RWTH Aachen,
Faculty 1
IL-10-induced tolerance in mast cells:
mechanisms and effects
E6-3
Martincuks,
A.
Ongoing RWTH Aachen,
Faculty 1
Cross-talk and subcellular localization
of NF-gB and STAT3
E6-7
Wiener, A.
Ongoing RWTH Aachen,
Biology
The influence of CREM alpha on B cell
activation and B cell/ T cell interations in
germinal centers of the spleen
E6-11
Asimakopoulos, A.
Ongoing RWTH Aachen,
Faculty 1
LCN2 in inflammatory liver disease
Ludwig Babendreyer, A.
Ongoing RWTH Aachen,
Biology
Assessment of leukocyte adhesion and
transmigration by impedance spectroscopy
Doctoral Theses
178
T2
Hoss, M.
Ongoing RWTH Aachen,
Faculty 1
Germline-derived pluripotent stem cells for
tissue engineering
T2
Qin, J.
Ongoing RWTH Aachen,
Faculty 1
Towards enhancing the differentiation
potential of human iPS cells
T3
Döring, Y.
2011
RWTH Aachen,
Faculty 1
Plasmacytoid dendritic cells and neurophils
underestimated cells populations during the
onset of atherosclerosis
T4
Sarabi, A.
2011
RWTH Aachen,
Biology
Structural and functional characterization
of the interactions of the platelet-derived
chemokines CCL5, CXCL4 and CXCL4L1
T5
Schmitt, M.
Ongoing RWTH Aachen,
Biology
Role and dynamics of JAM-A in atherogenic
inflammation
T6
Rongen, L.
Ongoing RWTH Aachen,
Faculty 1
In vitro and in vivo evaluation of the BioStent
T7
Schwarz, S.
Ongoing RWTH Aachen,
Faculty 1
Magnetic resonance imaging (MRI) with
engineered nanoparticles
T8
Ongoing RWTH Aachen,
Al
Rawashdeh,
Faculty 1
W.
IZKF Aachen Progress Report 2011
Combination of Optical Coherence
Tomography (OCT) and Near-InfraRedFunctional Optical Tomography (NIRF-OT)
for improving diagnosis in carcinoma
Funding Young Researcher
2011
RWTH Aachen,
Faculty of Electrical
Engineering
|
Diploma theses, Doctoral theses, Postdoctoral lectures
T8
Kray, S.
T9
Adamzyk, C. Ongoing RWTH Aachen,
Matrix-based bone substitutes using
Institute of Pathology mesenchymal stem cells
T9-2
Krull, P.
Ongoing RWTH Aachen,
Faculty 1
T9-2
Kant, S.
Ongoing RWTH Aachen,
Alterations in adhesion and signaling
Faculty of
of mutant desmoglein 2 as inducers of
Mathematics,
cardiomyopathy
Computer Science
and Natural Sciences
K1
Li, X.
Ongoing RWTH Aachen,
Faculty 1
The molecular effects of biofunctional
pro-EPC mini stents
K1
NazariJahantigh,
M.
Ongoing RWTH Aachen,
Faculty 1
EPC subpopulations and endothelial
function after stent implantation
K1
Subramanian, P.
Ongoing RWTH Aachen,
Faculty 1
EPC subpopulations and endothelial
function after myocardial infarction
K1-2
Kroh, A.
Ongoing RWTH Aachen,
Faculty 1
Myocardial regeneration after transplantation of modified endothelial progenitor cells
in a rat model of myocardial infarction
K1-2
Konschalla,
S.
Ongoing RWTH Aachen,
Faculty 1
The role of SDF-1 after endothelial
progenitor cells transplantation in a mouse
model of myocardial infarction
K1-3
Borinski, M.
Ongoing RWTH Aachen,
Faculty 1
Development and characterization of
polymer-based proendothelial stents
K1-4
Kanzler, I.
Ongoing RWTH Aachen,
Faculty 1
Therapeutic potential of MIF in angiogenesis: novel insights and comparison
with established angiogenic factors
K1-4
Gaffga, H.
Ongoing RWTH Aachen,
Faculty 1
Imaging and mechanisms of leukocyte
recruitment induced by MIF
K1-5
Simsekyilmaz, S.
Ongoing RWTH Aachen,
Faculty 1
Evaluation of biofunctionalized, covered
mini-stents in mouse-model
K3
Römer, A.
Ongoing RWTH Aachen,
Faculty 1
Cutaneous application of acidified or
pH-neutral nitrite: Nitric oxide but not nitrite
rapidly penetrates human epidermis and
alters local and systemic status of nitrogen
oxide species in vivo
K3
Vukadinović- Ongoing RWTH Aachen,
Faculty 1
Walter, B.
3.4.
Novel non-mechanical detection schemes
for optical coherence tomography
Correlation of osteopontin expression with
lesions and aseptic inflammation in the
heart of desmoglein 2 mutant mice
UVA-induced phenoxyl radical formation:
A new cytotoxic principle in photodynamic
therapy
IZKF Aachen Progress Report 2011
179
3.4.
180
Funding Young Researcher
|
Diploma theses, Doctoral theses, Postdoctoral lectures
K3
Rösner, J.
Ongoing RWTH Aachen,
Faculty 1
Redox-depend metal induced nitric oxid
formation
K3
Gombert, A.
Ongoing RWTH Aachen,
Faculty 1
Method for the measurement of antioxdative
capacity in human blood plasma via nitric
oxide formation
K3
Müller, T.
Ongoing RWTH Aachen,
Faculty 1
Evaluation of nitric oxide release from
aqueous solution for medical proposes
K3
Roser, S.
Ongoing RWTH Aachen,
Faculty 1
Safety of dermal application of nitric oxide
K5
Kanzler, I.
Ongoing RWTH Aachen,
Faculty 1
Therapeutic potential of MIF in angiogenesis: novel insights and comparison
with established angiogenic factors
K5
Strüßmann,
T.
Ongoing RWTH Aachen,
Faculty 1
Activation of MIF secretion from platelets
by thrombogenic stimuli
K5
Wirtz, T.
Ongoing RWTH Aachen,
Faculty 1
Role of platelet MIF in atherosclerosis
N1-1
Bauschulte,
J.H.
Ongoing RWTH Aachen,
Faculty 1
Effects of lysophosphatic acid on nerve
growth factor and tropomyosin-related
kinase A receptor signal transduction
N1-1
Meinhardt, A. Ongoing RWTH Aachen,
Faculty 1
Genotype-phenotype correlation in
neuropathies due to MPZ mutation
N1-1
Katona, I.
Ongoing RWTH Aachen,
Faculty 1
Pathogenesis of HSANs
N1-1
Wagner, S.
Ongoing RWTH Aachen,
Faculty 1
ALS: Clinico-neuropathological correlations
N1-1
Bushuven,
E.
Ongoing RWTH Aachen,
Faculty 1
VAPB in the pathogenesis of ALS
N1-1
Nikolin, S.
Ongoing RWTH Aachen,
Faculty 1
Patterns of characteristic muscle fiber
alterations in ALS
N1-2
Schmitz, S.
2011
RWTH Aachen,
Faculty 1
Isoform expression of cytochrome c oxidase
subunits and its influence on mitochondrial
function
N1-2
Römges, A.
Ongoing RWTH Aachen,
Faculty 1
Chemical hypoxia shows sex- and brain-region
specific differences of astrocyte survival and
transcription of cytochrome oxidase subunit IV
N1-3
Flick, F.
Ongoing RWTH Aachen,
Institute of Biochemistry and
Molecular Biology
Regulation of the NAD+-dependent
deacetylase SIRT2 by CDK5
IZKF Aachen Progress Report 2011
Funding Young Researcher
|
Diploma theses, Doctoral theses, Postdoctoral lectures
N2
Pohl, A.
Ongoing RWTH Aachen,
Dept. of Psychiatry,
Psychotherapy and
Psychosomatics
Mirror Neurons and Imitation of Dynamic
Facial Expressions: An fMRI Study
N2-1
Ruf, C.
Ongoing Maastricht,
Faculty
of Psychology
Assessing behavioral problems in children
in care
N2-3
Klasen, M.
2011
RWTH Aachen,
Dept. of Psychiatry,
Psychotherapy and
Psychosomatics
Virtual reality as stimulus material in the
social neurosciences
N2-4
Thönnessen, 2011
H.
RWTH Aachen,
Dept. of Psychiatry,
Psychotherapy and
Psychosomatics
Pre-attentive processing of prosody in
schizophrenia
N2-6
Schneider,
D.
Ongoing University Hospital
Aachen,
Department of
Psychiatry,
Psychotherapy and
Psychosomatics
Empathic behavioural and physiological
responses to dynamic stimuli in depression
N2-6
Regenbogen, C.
Ongoing University Hospital
Aachen,
Department of
Psychiatry,
Psychotherapy and
Psychosomatics
Multimodal human communication – targeting facial expressions, speech content and
prosody
N3
Mühlhaus, J. Ongoing RWTH Aachen,
Department of
Psychiatry,
Psychotherapy and
Psychosomatics
Neural correlates of the impact of semantic
associations on sentence production
N4-1
Vloet, T.
Ongoing RWTH Aachen,
Faculty of Medicine
Neurobiological aspects of antisocial
disorders
N4-1
Grossheinrich, N.
Ongoing RWTH Aachen,
Faculty of Medicine
Development of affective dysregulation in
children and adolescents at risk
N4-3
Gysemans,
L.
Ongoing RWTH,
Faculty of Medicine,
Neuroradiology
Impact of chemosensory signals during
communication of aggression in humans
N4-4
Bischoff, B.
Ongoing RWTH Aachen,
Department of
Psychiatry,
Psychotherapy, and
Psychosomatics
Impulsivity and MAO-A genotype
IZKF Aachen Progress Report 2011
3.4.
181
3.4.
182
Funding Young Researcher
|
Diploma theses, Doctoral theses, Postdoctoral lectures
N5-2
Flick, F.
Ongoing RWTH Aachen,
Institute of
Biochemistry and
Molecular Biology
Regulation of the NAD+-dependent deacetylase SIRT2 by CDK5
N5-2
Otten, D.
Ongoing RWTH Aachen,
Institute of
Biochemistry and
Molecular Biology
Function of SIRT2 in neurodegenerative
disorders
N5-3
Bauschulte,
J.H.
Ongoing RWTH Aachen,
Faculty of Medicine
Effects of lysophosphatic acid on nerve
growth factor and tropomyosin-related
kinase A receptor signal transduction
N5-3
Meinhardt, A. Ongoing RWTH Aachen,
Faculty of Medicine
Genotype-phenotype correlation in neuropathies due to MPZ mutation
N5-3
Katona, I.
Ongoing RWTH Aachen,
Faculty of Medicine
Pathogenesis of HSANs
N5-3
Wagner, S.
Ongoing RWTH Aachen,
Faculty of Medicine
ALS: Clinico-neuropathological correlations
N5-3
Bushuven,
E.
Ongoing RWTH Aachen,
Faculty of Medicine
VAPB in the pathogenesis of ALS
N5-3
Nikolin, S.
Ongoing RWTH Aachen,
Faculty of Medicine
Patterns of characteristic muscle fiber
alterations in ALS
N6
Bresenitz, P. Ongoing RWTH Aachen,
Faculty of Medicine
E1-1
Janssen, J.
E1-1
Bettermann, 2011
K.
RWTH Aachen,
The role of TAK1 in liver cancer
Faculty of
Mathematics,
Computer Science
and Natural Sciences
E1-4
Lettow, I.
2011
RWTH Aachen,
Faculty of Medicine
A Duffy antigen receptor for chemokines
(DARC) polymorphism that determines
pro-fibrotic chemokine serum concentrations
is not directly associated with progression
of hepatitis C infection
E2
Ohl, K.
2011
RWTH Aachen,
Biology
Regulation of the immune response by
CREM alpha
E2
Honke, N.
Ongoing RWTH Aachen,
Biology
IZKF Aachen Progress Report 2011
Modulation of Acid-Sensing Ion Channels
by NH4+
Ongoing RWTH Aachen,
Molecular mechanisms of hepatic
Faculty of
Ischemia/Reperfusion injury
Mathematics,
Computer Science
and Natural Sciences
Posttranscriptional regulation of gp130 in
cells of the immune system
Funding Young Researcher
|
Diploma theses, Doctoral theses, Postdoctoral lectures
E3
Sicking, E.
Ongoing Essen,
Veterinary Medicine
The functional role of PECs in acute
glomerular disease
E4
Giebeler, A.
2011
RWTH,
Faculty of Medicine
HGF/c-Met and IL-6/gp130 mediated
signalling pathways in a model of acute and
chronic cholestatic liver injury in mice
E5
Rüland, A.
2011
RWTH Aachen,
Faculty of Medicine
Functional relevance of the chemokine
RANTES in liver fibrosis
E6-1
Dohmen, M. Ongoing RWTH Aachen,
Medical School
Investigation of the TLR4-induced autophagy pathway downstream of p38:
Connection to cell cycle
E6-2
Kuhny, M.
2011
IL-1-type cytokines and mast cells:
Induction of proinflammatory responses
and a non-canonical release mechanism
E6-2
Poplutz, M.
Ongoing RWTH Aachen,
Faculty 1
Reprogramming of the allergic mast cell
response by low-dose endotoxin
E6-3
Rinis, N.
Ongoing RWTH Aachen,
Faculty 1
Anti-inflammatory activity of persistently
activated STAT3
E6-9
Hess, F. M.
Ongoing RWTH Aachen,
Biology
Role of the metalloproteinases ADAM10
and ADAM17 for leukocyte migration
E6-9
Nagel, P.
Ongoing RWTH Aachen,
Medicine
In vitro and in vivo assessment of
ADAM10 and ADAM17 function by inhibitory
prodomains
E6-11
Lux, S.
Ongoing RWTH Aachen,
Faculty 10
Functional analysis of CCN proteins in
hepatic fibrogenesis
E6-11
Bultmann, C. Ongoing RWTH Aachen,
Faculty 10
Regulation and function of the LIM domain
proteins CRP2 and FHL2 in experimental
models of liver injury
E6-11
Alexi, P. H.
The role of TGF-` and PDGF isoforms in
inflammatory liver diseases
E6-11
Boaru, S. G. Ongoing RWTH Aachen,
Faculty 1
Expression analysis of inflammasome
components in models of inflammatory liver
disease
Thumann
Harmening,
N.
Ongoing RWTH Aachen,
Faculty 1
MRNA based SB transfection of primary
cells
Thumann
Salz, A.
2011
RWTH Aachen,
Faculty 1
In vitro and in vivo studies of pigment
epithelial cells and biomaterials for
subretinal transplant development
Thumann
Gaebler, A.
2011
RWTH Aachen,
Faculty 1
Biocompatibility of a collagen type I membrane in the subretinal space
University of
Freiburg,
Faculty of biology
Ongoing RWTH Aachen,
Faculty 1
IZKF Aachen Progress Report 2011
3.4.
183
3.4.
Funding Young Researcher
|
Diploma theses, Doctoral theses, Postdoctoral lectures
Thumann
Frank, D.
2011
RWTH Aachen,
Faculty 1
Collagen foil as a carrier for cell transplantation into the subretinal space in order to
replace RPE in AMD
Thumann
Bertram, P.
Ongoing RWTH Aachen,
Faculty 1
Characterization of the genomic stability in
non-virally transfected primary cells
Thumann
Möller, T.
Ongoing RWTH Aachen,
Faculty 1
The Anti-Angiogenic Effect of recombinant
PEDF in vitro
Ludwig Schumacher, Ongoing RWTH Aachen,
J.
Biology
Role of ADAM17 in experimental lung
fibrosis
Ludwig Koenen, A.
Ongoing RWTH Aachen,
Biology
Role of CXCL16 and its cleaving
metalloproteinases in experimental
lung allergy
Ludwig Groth, E.
Ongoing RWTH Aachen,
Biology
Regulation of ADAM17
Postdoctoral lecture qualification
184
K1-1
Hristov, M.
K1-4
El Bounkari, Ongoing RWTH Aachen,
O.
Faculty 1
Physiology and pathophysiology of MIF
receptor complexes
K1-4
Simons, D.
CXCR4-based recruitment and metastasis
processes
K3
Opländer, C. Ongoing RWTH Aachen,
Faculty 1
Nonenzymatic nitric oxide generation in
physiology and therapy
K5
von
Hundelshausen, P.
Ongoing LMU Munich
Thrombogenic chemokines
N1-1
Claeys, K.
2011
RWTH Aachen,
Faculty 1
Clinico-pathological characterization
and genotype-phenotype correlations in
hereditary neuromuscular disorders
N2-5
Domahs, F.
2011
University of
Potsdam,
Faculty of
Human Sciences
Impairments of verbal fact knowledge
E4
Giebeler, A.
Ongoing RWTH Aachen,
Faculty 1
IZKF Aachen Progress Report 2011
2011
RWTH Aachen,
Faculty 1
Ongoing RWTH Aachen,
Faculty 1
The role of circulating angiogenic cells in
endothelial regeneration and vascular risk
predictionv
HGF/c-Met and IL-6/gp130 mediated
signalling pathways in a model of acute and
chronic cholestatic liver injury in mice
3.4.
IZKF Aachen Progress Report 2011
185
C O R E L A B O R AT O RY
p. 188
C H I P FA C I L I T Y
p. 191
IMMUNOHISTOCHEMISTRY AND CONFOCAL
L A S E R S C A N N I N G M I C R O S C O P Y FA C I L I T Y
p. 196
B R A I N I M A G I N G FA C I L I T Y
p. 200
T W O - P H O TO N I M A G I N G FA C I L I T Y
p. 204
TRANSGENIC SERVICE
p. 207
C O R E FA C I L I T I E S
Equipment and Expertise – Service for Research
In 2011, the IZKF funded central equipment and expertise with
€ 1,107,488. These Core Facilities are available to all members of
the Faculty of Medicine.
4.1.
Core Facilities
|
Core Laboratory
Core Laboratory
Heads of the Core Laboratory:
Thumann G.
Ludwig A.
Safety delegate / assistant project supervisor for genetic engineering security:
Zwadlo-Klarwasser G.
Project supervisor for genetic engineering security:
Denecke B.
Services
In the Core Laboratory various equipment is
provided, that is not correlated to any Core Facility. Like the Core Facilities, the equipment is not
only available for IZKF project heads or project
personnel, but for all the members of the Faculty
of Medicine. The equipment also can be used
upon request by RWTH scientists. The Core
Laboratory provides infrastructure, lab space and
know-how. The personnel of the Core Laboratory
provides services for research, assistance to use
User of the Core Laboratory
the equipment and advises in all scientific issues.
The concept aims at handling organizational and
technical-methodical challenges and assisting the
project personnel. Furthermore the centralization
of equipment and expertise aims at conserving
resources. Synergetic effects emerge from the
collaboration of researchers and Core Facilities
and these effects are useful for the two-way technical-methodical assistance that keeps research
and service at the highest level.
In 2011 the Core Laboratory was used by 183 employees of several institutes and clinics.
188
IZKF Aachen Progress Report 2011
Core Facilities
|
Core Laboratory
4.1.
Staff: 1 TV-L 14 (Zwadlo-Klarwasser G.)
½ TV-L 9 (Kratz B.)
7 h TV-L 9 (Tappe M.)
Materials 2011: € 47,130
Investments/Equipment 2011: € 25,000
Equipment and contact persons
All equipment and laboratories can be used upon request and after having consulted the IZKF
administration office and the responsible contact person.
Mikroscopes
Kratz B. / Ensslen S.
Western Blot Documentation System LAS 3000
Kratz B.
Flow Cytometry: FACS Calibur/FACS Canto
Tappe M.
Agilent Bioanalyser 2100
Kratz B.
7300 Real Time PCR Taq Man
Denecke B./ Kratz B.
Fluorostar Optima
Kratz B.
Nanodrop
Kratz B.
Photometer
Tappe M.
HPLC/FPLC
Preisinger C.
MALDI-TOF System
Preisinger C.
Geldoc – DNA and Protein
Ensslen S.
Autoclaves
Tappe M.
MilliQ Equipment
Kratz B.
Cell Culture Laboratory
Kratz B.
Constant Temperature Laboratory
Denecke B.
IZKF Aachen Progress Report 2011
189
4.1.
Core Facilities
|
Core Laboratory
Usage of the equipment
Following overview shows a selection of the equipment of the Core Laboratory and their usage in 2011:
Equipment
Mikroscopes
LAS3000 (Western Blot)
FACS Canto
Agilent
Nanodrop
Cell Culture Laboratory
HPLC/FPLC
Taq Man
190
IZKF Aachen Progress Report 2011
Using Clinics/Institutes
18
14
10
3
11
5
3
7
Total appointments
788
864
1008
67
485
392
41
298
Core Facilities
Staff:
|
Chip Facility
4.2.
1 TV-L14 (Denecke B.)
¾ TV-L13 (Gan L.)
1 TV-L 9 (Kashani A.)
½ TV-L 9 (Kratz B.)
Materials 2011: € 25,930
Investments/Equipment 2011: –
Revenues 2011: € 26,694
Chip Facility
Head of the facility:
Scientific supervision:
Denecke B.
Zenke M. (IBMT – Cell Biology)
Services
Experimental consulting - assistance through optimization of the experimental design, cost analysis, planning and implementation of the experiments (individual schedule)
Sample preparation - cell culture, tissue, and
blood probes; sample preparation in accordance
with favourite standard procedures (total RNA,
mRNA, miRNA, DNA, protein)
Quality control - analyses of DNA, RNA, and
protein using the 2100 Bioanalyzer microfluidics-based platform (Agilent); quantification using NanoDrop technology; the pretesting of the
probes using a „test-chip“ is also possible.
Sample preparation - chip and detection specific,
respectively. During the labelling procedures all
steps are monitored by analyses of the intermediate products, internal spike controls and polyA+
controls are applied
(RNA analyses).
Hybridization - Hybridization (including internal controls), washing
steps, antibody-staining,
scanning of the arrays
according to SOPs.
Data analysis (I) - primary evaluations, preparation of report files,
analyses of most important reference genes,
transfer to an Excelcompatible file format.
Recording of the array
experiments - according
the MIAME (Minimum
Information About a
Microarray Experiment)
standard.
Data analysis (II) - secondary interpretation:
depending on the kind
of array used: (gene ontologies, pathways, network interactions, splicing variants, single nucleotide polymorphisms, copy number variants,
insertions/deletions, segmental duplications, localizations of bound proteins, etc.).
Additional comments - particular attention must
be paid to the careful design of the experiments,
a standardized isolation, further treatment, and
storage of the material to be analysed.
Furthermore, a number of intensive individual
consulting conversations were conducted (possibilities of and limits to the use of the array technology, experimental design, data interpretation,
publication of array data, etc.).
See also Figure 1 and homepage of the Chip-facility: http://www.chip-facility.rwth-aachen.de/
Fig. 1: Chip Facility Performances
IZKF Aachen Progress Report 2011
191
4.2.
Core Facilities
|
Chip Facility
User
User within the faculty
• Department of Anaesthesiology (Röhl A.B.)
• Department of Anaesthesiology, Institute of Pharmacology and Toxicology (Dassow C., Uhlig S.)
• Department of Biomedical Engineering, Biointerface Laboratory (Jahnen-Dechent W., Pan Y.)
• Department of Cardiology, Pneumology,
Angiology and Internal Medicine Intensive Care - Internal Medicine I (Kelm M., Steinmetz E.L.)
• Department of Dental Preservation (Apel C., Smeets R., Buttler P.)
• Department of Dermatology and Allergology (Baron J.M., Merk H.F., Felbert V.)
• Department of General-, Visceral- and Transplantation Surgery (Lynen-Jansen P., Neumann U.P.)
• Department of Nephrology and Clinical Immunology - Internal Medicine II (Mertens E., Ostendorf
T., Rauen T., v. Royen C., Villa L., Kunter U., Kuppe C., Möller M., Mühlfeld A., Raffetseder U.)
• Department of Paediatric and Adolescent Medicine (Tenbrock K., Ohl K.)
• Department of Plastic Surgery, Hand and Burns Surgery (Hemmrich K.)
• Gastroenterology and Metabolic Disorders - Internal Medicine III
(Berger K., Lüdde T., Liedtke C., Roderburg C.)
• Haematology and Oncology - Internal Medicine IV (Ziegler P., Gökkurt E.)
• Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering
(Wagner W., Weidner C.)
• Institute for Biomedical Engineering - Cell Biology
(Hieronymus T., Zenke M., Baek J.H., Ding X., Sere K., Fleischer J.)
• Institute for Medical Psychology (Krag C.)
• Institute for Molecular Cardiovascular research
(Schumann U., Jahntish M.N., Schober A., Wei Y., Noels H.)
• Institute of Biochemistry and Molecular Biology (Lüscher-Firzlaff J.M., Lüscher B., Hartkamp J.)
• Institute of Biochemistry and Molecular Biology,
Department of Biochemistry and Molecular Immunology (Huber M., Hochdörfer T.)
• Institute of Human Genetics (Eggermann T., Spengler S.)
• Institute of Molecular and Cellular Anatomy (Krusche C.)
• Institute of Neuroanatomy
(Beckmann R., Gingele S., Pott F., Dang J., Kipp M., Arnold S., Fahlenkamp A., Beyer C., Johann S.)
• Institute of Pathology (Neuss-Stein S.)
• Interdisciplinary Center of Clinical Research Aachen (Zwadlo-Klarwasser G., Hoss M., Bartnek M.)
• Molecular Oncology Group, Institute of Pathology (Dahl E.)
• Surgical Intensive Care - Adults (Marx G., Ostarek D., Ostarek-Lederer A.)
Dropped users (no longer working at UKA) within the faculty
• Department of Biomedical Engineering, Biointerface Laboratory (Schäfer C.)
• Department of Dermatology and Allergology (Wiederholt T.)
• Department of Nephrology and Clinical Immunology - Internal Medicine II
(Hempfing G.B., Westenfeld R.)
• Department of Ophthalmology (Franke T.)
• Department of Plastic Surgery, Hand and Burns Surgery (Hofmeister D.)
• Department of Urology (Becker C.)
• Institute for Biomedical Engineering - Cell Biology
(Ober-Blöbaum J., Baden S., Jaenti P., Ensenat-Waser R.)
• Institute of Biochemistry and Molecular Biology (Hein N., Heinrich P.)
• Interdisciplinary Center of Clinical Research Aachen (Döll M., Wöltje M.)
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Chip Facility
4.2.
IZKF Aachen Progress Report 2011
193
External user (RWTH, other users)
• Department of Applied Microbiology (Hoffmann K.)
• Department of Plant Physiology - Bio III (Delventhal R., Löhrer M.)
• Department of Zoology and Animal Physiology (Kampmann E., Mey J.)
Collaborations (with external partners or industrial partners)
• Axiogenesis AG Cologne (Kettenhofen R., Tressat K.)
• Center for Pharmacology and Toxicology, University Medical Center Göttingen
(Zimmermann W.-H.)
• Department for Cell Morphology and Molecular Neurobiology, Ruhr-University Bochum
(Reinhard J., Karus M., Faissner A.)
• Department of Cell and Developmental Biology,
Max Planck Institute for Molecular Biomedicine, Münster (
Kim J.B., Kinarm K.o.K., Sterneckert J., Sutter J., Schölar H.R., Sinohara T.)
• Department of Chemical Oncology, University of Duesseldorf (Bojar H., Röder G.)
• Department of Immune Modulation, University Hospital Erlangen (Steinkasserer A.)
• Department of Systems Biology, Otto-von-Guericke- University (Schaper F.)
• Faculty of Technology - AG Cell Culture technique, Bielefeld University (Noll T.)
• Institut für Medizinische Strahlenkunde und Zellforschung,
Julius-Maximilians-Universität Würzburg Germany
• Institute for Anatomy and Cellbiology, Ulm University (Liebau S.)
• Institute for Prevention of Cardiovascular Disease, Ludwig-Maximilians-University, Munich
(Weber C., Bidzhekov K.)
• Institute for Transfusion Medicine, Charité - Universitätsmedizin Berlin (Moldenhauer A.)
• Institute of Anatomy, University of Cologne (Arnold S.)
• Institute of Biochemistry - Unit for Stem Cell Biology,
Asymmetric Cell Division and Virus-Cell-Interaction (Just U., Schwabenbeck R., Meier-Stiegen F.)
• Institute of Farm Animal Genetics, Friedrich-Loeffler-Institut (FLI), Neustadt
(Herrmann D., Kues W., Niemann H.)
• Institute of Immunology, Witten/Herdecke University (Dittmar T.)
• Institute of Molecular Biology, University of Zurich (Baudis M.)
• Institute of Neurology - Edinger-Institute - Restorative Neurology,
Johann Wolfgang Goethe-University Frankfurt (Momma S.)
• Institute of Virology, Center of Molecular Medicine,
University of Cologne, Cologne, / Institute of Virology, Saarland University, Homburg/Saar
(Smola S.)
• Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO)
at Hannover Medical School (Jara-Avaca M.)
• Life & Medical Sciences Institute Bonn - LIMES - Bonn University (Staratschek-Jox A.)
• Max Planck Institute for Brain Research, Frankfurt (Betz H., Weltzien F.)
• Max Planck Institute of Molecular Cell Biology and Genetics - MPI-CBG, Dresden (O´Sullivan G.)
• Molecular Endocrinology - Medical Clinic III, Carl Gustav Carus University Medical School,
Dresden University of Technology, Dresden (Ehrhardt-Bornstein M., Vukicevic V.)
• MSZ and Center for Experimental Molecular Medicine (ZEMM), University of Wuerzburg,
Wuerzburg (Li X., Obier N., Müller A.M., Vallabhapuapn D.)
• Regenerative Biology and Reconstructive Therapies, acronym REBIRTH,
Hannover Medical School (Schmeckebier S.)
• Stem Cell Engineering Group, Institute of Reconstructive Neurobiology,
LIFE and BRAIN Center, University of Bonn (Nolden L., Haubenreich C.)
4.2.
Core Facilities
|
Chip Facility
Publications
IZKF relevant, project associated
1. Karus, M.; Denecke, B.; ffrench-Constant, C.; Wiese, S.; Faissner, S. (2011)
The extracellular matrix molecule tenascin C
modulates expression levels and territories of
key patterning genes during spinal cord astrocyte specification. Development, 138 (24)
5321-5331. [IF 6.898]
2. Gan, L.; Schwengberg, S.; Denecke, B. (2011)
Micro RNA profiling during cardiomyocytespecific differentiation of murine embryonic
stem cells based on two different miRNA array
platforms. Plos One, 6 (10) e25809. [IF 4.411]
3. Schellenberg , A.; Lin, Q.; Schüler, H.; Koch,
C.M.; Joussen, S.; Denecke, B.; Walenda, G.;
Pallua, N.; Suschek, C.V.; Zenke, m.; Wagner,
W. (2011) Replicative senescence of mesenchymal stem cells causes DNA-methylation
changes which correlate with repressive histone marks. AGING (Albany NY), 3 (9) 873888. [IF 2.964]
4. Neuss, S.; Denecke, B.; Gan, L.; Lin, Q.; Bovi,
M.; Apel, C.; Wöltje, M.; Dhanasingh, A.; Salber, J.; Knüchel, R.; Zenke, M. (2011) Transcriptome analysis of MSC and MSC-derived
osteoblasts on Resomer® LT706 and PCL:
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IZKF Aachen Progress Report 2011
Impact of biomaterial substrate on osteogenic
differentiation. PLoS One, 6 (9) e23195. [IF
4.411]
5. Khouri, C.; Dittrich, A.; Sackett, S.D.; Denecke, B.; Trautwein, C.; Schaper, F.:
Glucagon counteracts interleukin-6-dependent
gene expression by redundant action of Epac
and PKA (2011) Biological Chemistry, 392,
1123-1134. [IF 3.603]
6. Kipp, M.; Gingele, S.; Pott, F.; Clarner, T.; van
der Valk, F.; Denecke, B.; Gan, L.; Siffrin, V.;
Zipp, F.; Dreher, W.; Baumgartner, W.; Pfeifenbring, S.; Godbout, R.; Amor, S.; Beyer, C.
(2011) BLBP-expression in astrocytes during
experimental demyelination and in human
multiple sclerosis lesions. Brain, Behavior, and
Immunity, 25 (8) 1554-1568. [IF 3.956]
7. Villa, L.; Boor, P.; Koniecnzy, A.; Kunter, U.; van
Roeyen, C.R.; Denecke, B.; Gan, L.; Kupper,
M.B.; Hoffmann, K.; Eitner, F.; Ostendorf, T.;
Floege, J. (2011) Effects and mechanisms of
angiotensin II receptor blockade with telmisartan in a normotensive model of mesangiooroliferative nephritis. Nephrology Dialysis Transplantation, 26 (10) 3131-3143. [IF 3.564]
Core Facilities
|
Chip Facility
4.2.
Fig. 2: Development of the chip-facility since establishment
IZKF Aachen Progress Report 2011
195
4.3.
Core Facilities
|
Immunohistochemistry & Confocal Laser Scanning Microscopy Facility
Immunohistochemistry &
Confocal Laser Scanning Microscopy Facility
Head of the facility:
Scientific supervision:
Ensslen S.
Müller-Newen G. (Institute of Biochemistry and Molecular Biology)
Knüchel-Clarke R. (Institute of Pathology)
Lüscher B. (Institute of Biochemistry and Molecular Biology)
Services – Immunohistochemistry
At the immunhistological facility of the IZKF
Aachen, researchers can order all technical services necessary for histological and immunhistological experiments.
The following services are available:
• pre-experimental consulting
• support in excision and preparation of samples
and tissues (choice of proper fixatives)
• dehydration and embedding of fixed tissues
• preparation of tissue slices (paraffin and cryo)
• histological staining (H&E, EvG, Giemsa, PAS
etc.), direct and indirect immunhistological
staining
• testing of antibodies (according to prior agreement)
• microscopy and documentation (according to
prior agreement)
At the Institute for Pathology existing immunostainer can also be used to perform immunhistochemical staining with more than 70 well-established antibodies.
In 2011, 78 researchers from 28 different clinics/
institutes of Faculty of Medicine at RWTH Aachen
and 4 researchers from external institutes used
the immunhistological facility. A total of 12,155
tissue samples were dehydrated and embedded.
13,869 slices were produced and 4,474 slides
were stained. 432 immunohistological staining
procedures were performed.
Even though as a whole, more orders were executed in 2011 (fig. 1) than in 2010, in the second half of the year the number of ordered tissue slices and histological staining experiments
decreased (12% fewer slices and 13.5% fewer
staining; fig. 2), perhaps due to increasing costs
since 1st of July 2011.
In 2011, we enhanced our equipment. We bought
a new rotation microtome and put two slice-transfer-systems into operation that allow the fabrication of pretty thin and constant paraffin slices.
Furthermore we invested in a Cover Tec Microm
CTM6, which can be used to cover slides at very
short times and with an excellent effect.
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Core Facilities
|
Immunohistochemistry & Confocal Laser Scanning Microscopy Facility
Staff:
4.3.
1 TV-L14 (Ensslen S.)
½ TV-L 13 (Fahrenkamp D.)
½ TV-L 9 (Tappe M.)
1 TV-L 8 (Wüffel J.)
Materials/Travel expenses 2011: € 18,000
Investments/Equipment 2011: € 5,000
Revenues 2011: € 17,600 (used for consumable materials, machine care and repairing)
User
Users within the faculty:
• Department of Anaesthesiology (Röhl A.)
• Department of Ophthalmology
(Bierwagen J., Bozlu L., Etzkorn C., Kazanskaya O., Kürten D., Pollmann L., Salz A., Thumann G.)
• Department of Surgery (Nolting J.)
• Department of Vascular Surgery (Greiner A., Kokozidou M., Westhofen S., Zaragatski E.)
• Department of Paediatric and Adolescent Medicine (Schippers A., Schmitz C., Tenbroeck K.)
• Department of Dermatology (Heise R., Megahed M.)
• ZMKPG (Smeets R.)
• Internal Medicine I (Marx N.)
• Internal Medicine II (Bataille N., Dietzel G., Fuß A., Hanßen L., Härthe K., Krüger T., Kunter U.,
Moeller M., Mühlfeld A., Ostendorf T., Raffetseder U.)
• Internal Medicine III (Bartneck M., Ehedago H., Erschfeld S., Liedtke C., Nevzorova J., Singh L.,
Streetz K., Tacke T., Trautwein Ch., Zimmermanns L.)
• Surgical Intensive Care (Schürholz T.)
• Department of Orthopaedics (Gavenis C., Lecouterieur S., Rath B.)
• Department of Plastic, Hand and Burns Surgery (Bozkurt A., Grieb G., Paul N., Suscheck Ch.)
• Department of Trauma Surgery (Kobbe P.)
• Department of Urology (Grosse J., Läufer T., Montzka K.)
• Department of Dental Preservation (Buttler P.)
• Helmholtz-Institute for Biomedical Engineering (Applied Medical Engineering)
(Jockenhövel S., Steinseifer U.)
• Institute of Biochemistry (Schütz A.)
• Helmholtz-Institute for Biomedical Engineering (Cell Biology)
(Brylka L., Dietzel E., Elsas J., Herrmanns M., Jahnen-Dechent W., Kinkeldey A.;)
• Institute of Immunology (Haase H.)
• Institute of Clinical Chemistry and Pathobiochemistry (Borkham E.)
• Institute for Molecular Cardiovascular Research
(Akhter Sh., Garbe M., Jahantigh M., Li X., Schober A., Subramanian P., Wilbertz S., Zhou B.)
• Institute of Pharmacology and Toxicology (Dreymüller D., Rieg A., Uhlig S., Verjahns E.)
• Institute of Physiology (Gründer S., Polleichter G., Reska A.)
• Institute of Laboratory Animal Science (Afiffy A., Paschenda P., Tolba R.)
• Helmholtz-Institute for Biomedical Engineering (Cell Biology) (Zenke M.)
• Interdisciplinary Center for Clinical Research Aachen (Denecke B., Ensslen S.)
External user:
• ACTO (Panfield C.)
• Imaging Sciences, St. Thomas, the Rayner’s Institute, London
(Butzbach B., Phinikaridou A., Vondermuehle A.)
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4.3.
Core Facilities
|
Immunohistochemistry & Confocal Laser Scanning Microscopy Facility
On 1 st July 2011, the core facility “Immunohistochemie” was extended and relaunched as “Immunohistochemistry & Confocal Laser Scanning Microscopy”. The following section reports on the activities of
the confocal microscopy subunit.
Services – Confocal laser scanning microscopy
• pre-experimental consulting
confocal imaging:
• 2-dimensional confocal imaging
– multi-channel images
– exact overlay of differential interference
contrast (DIC) with confocal images
– analysis of colocalization
– fluorescence intensity profiles
• 3-dimensional confocal images
– preparation of optical slices (“z-stacks“)
– reconstruction of 3-dimensional objects
F-techniques:
• FRAP (fluorescence recovery after photobleaching) and FLIP (fluorescence loss in
photobleaching) to determine the mobility of
fluorescent proteins in living cells including
diffusion constants.
• FLAP (fluorescence localization after photobleaching) to analyze the shuttling of fluorescently labelled molecules between subcellular
compartments.
• FRET (fluorescence resonance energy
transfer) to detect the interaction between
fluorescently labelled molecules with high
spatial resolution in fixed cells or with temporal resolution in living cells.
• BiFC (bimolecular fluorescence complementation) to detect the interaction of specifically
labelled proteins.
• Use of photoactivatable or photoconvertible
fluorescent proteins to detect the dynamics of
proteins in living cells.
User
Users within the faculty:
• Institute of Biochemistry and Molecular Biology (Huber M., Lüscher B. and various coworkers)
• Institute of Biochemistry and Molecular Cell Biology (Bernhagen J. and various coworkers)
• Helmholtz-Institute for Biomedical Engineering (Cell Biology) (Hieronymus T., Zenke M.)
• Helmholtz-Institute for Biomedical Engineering (Biointerface)
(Pan-Bartneck Y., Dietzel E., Hamann M., Jahnen-Dechent W.)
• Institute of Clinical Chemistry and Pathobiochemistry
(Stellmacher C., Khlistuwova I., Weiskirchen R.)
• Institute of Neuropathology (Hodde D., Brook G., Goswami A., Katona I., Weis J.)
• Institute of Pathology (Schneider-Kramann R., Leisten I., Knüchel-Clarke R.)
• Department of Paediatric and Adolescent Medicine (Clahsen T., Wagner N.)
• Internal Medicine I (Ziegler P., Brümmendorf T.)
• Internal Medicine II (Braun G., Alidousty C., Klinkhammer B., Kunter U., Floege J.)
• Internal Medicine III (Bartneck M., Tacke F.)
External user:
• Institute of Anorganic Chemistry (Witten K., Simon U.)
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Core Facilities
|
Immunohistochemistry & Confocal Laser Scanning Microscopy Facility
4.3.
Publications
IZKF relevant, project associated
The confocal microscopy subunit has been funded for 6 months. Therefore, there are no publications that
refer to IZKF funding yet.
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Müller-Newen G. Directed immobilization of fluorescently DFG, GRK 1035
labelled cytokines
Biointerface
07/200406/2013
€ 20,000
p.a.
Müller-Newen G. Persistent activation of STAT transDFG,
cription factors in inflammatory cytokine Transregio-SFB
pathways and modulation of their
TRR 116
subcellular distribution by cross-talk
mechanisms
07/201206/2016
€ 100,000
p.a.
Müller-Newen G. Receptor fusion proteins for the
inhibition of cytokines in disease
11/201210/2016
€ 30,000
p.a.
EU, FP7-PEOPLE-2012-ITN
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4.4.
Core Facilities
|
Brain Imaging Facility
Brain Imaging Facility
Technical head of the facility:
Schnitker R.
Mingoia G.
Methodical head of the facility: Zvyagintsev M.
Scientific supervision:
Mathiak K.
(Department of Psychiatry, Psychotherapy and Psychosomatics)
Wiesmann M.
(Department of Diagnostic and Interventional Neuroradiology)
Willmes K. (Department of Neurology)
Services
Core Facility Brain Imaging provides comprehensive service for neuroscientific research related
to neuroimaging as well as neuro-psychological
sciences. Our service encompasses assistance
at all stages of performing successful experimental work such as preparing experiments, running
experiments, data analysis, and publication of
results. Within 2011, we extended the amount
of services provided within our facility. The major extensions were provided in the field of magnetic resonance imaging (MRI) related research
and especially in methods of MRI data analysis.
Particularly, we distinguish three fields of MRI
where our services were expanded: functional
MRI, structural MRI and Diffusion Tensor Imaging (DTI). In functional MRI we significantly increased the number of data analysis techniques.
We also offer our users support in using these
techniques. In addition to the previously provided
general linear modelling approach, we currently
offer support in multi voxel pattern analysis
technique (MVPA) and independent component
analysis (ICA). These methods allow our users
to address new research questions and improve
the quality of their research. We installed the
necessary software and we are constantly looking for the most advanced software available on
the market in order to make them available to our
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IZKF Aachen Progress Report 2011
users. All the analysis techniques were updated
and optimized and can be performed within a
shorter time frame. We also support our users in
the analysis of resting state data. This is a relatively new trend in neuroimaging which requires
special methods and analysis techniques which
we currently include in our services. Moreover,
we provide support in performing real-time fMRI
data analysis and fMRI-related neurofeedback
research. In addition, we can now better support
DTI related research. In particular, we optimized
the protocols for the DTI acquisitions and provide
support for the most popular software packages
currently used worldwide for analysis of DTI data.
More studies nowadays acquire DTI data and we
expect more extensive usage of DTI analysis in
the near future. Important extension is related to
the analysis of the structural MRI data. We provide support for Voxel-Based Morphometry and
Cortex Thickness Analysis approaches.
As concerns the training courses, we provide a
broader spectrum of courses within our facility. In
particular, we added two new courses: “Statistical
Parametric Mapping” (in English) and “Matlab for
Neuroscientists”. Moreover, we updated the programs of the running courses. In 2011, the developers of the software for neuroimaging research
organized several mini-workshops .
Core Facilities
|
Brain Imaging Facility
4.4.
Staff: 1 TV-L 14 (Schnitker R.), 1 TV-L 14 (Mingoia G.), 1 TV-L 14 (Zvyagintsev M.),
½ TV-L 13 (Schüppen A.), ½ TV-L 13 (Pustelniak M.), ½ TV-L 13 (Mols P.), ½ TV-L 13
(Schwenzer M.), 1 TV-L 11 (Weyer D.), 1 TV-L 10 (Eder G.), ½ TV-L 10 (Arnolds K./
Söndgen E.), ½ WHK (Kölzer F.), ½ SHK (Steiner D.), ½ SHK (Adigüzel K.), ½ SHK
(Heinrich I.), ½ SHK (Brieger J.), ½ SHK (Dinkel P.), ½ SHK (Hohlbaum K.)
Materials/Travel expenses 2011: € 11,800
Investments/Equipment 2011: € 28,100
Revenues 2011: –
User
User within the faculty
• Core Facility Brain Imaging
(Schüppen A., Vogel A., Winter A., Spataro A., Krug A., Steinhauer B., Voss B., Lehrenfeld C., Terhorst
C., Marjoram D., Greinel E., Gehring F., Eder G., Kohls G., Utting J., Weber J., Kukolja J., Heider K.,
Dressel K., Jüttemann K., Paheenthararajah K., Sanroman L., Wetzels M., Offermann M., Schaaf
M., Meister M., Breuer M., Zellagui N., Lejoly N., Sachs O., Schlotterbeck P., Mols P., Schnitker R.,
Abel S., Michels T., Markov V., Groß S., Zilch-Purucker B., Lenhardt G., Antweiler G., Krowatschek
G., Polmans K., Hoppe M., Mahr M., Jansen C., Groten R., Papageorgiou S., Erberich S., Steiner D.,
Leiberg S., Peters A., Michelsen I., Heinrichs M., Krach S., Kirner A., Sass K., Derntl B., Hauck J., Do
Lam A., Herl V., Kellermann T., Dautzenberg K., Vaeiraenen A., Pustelniak M., Rademacher L., Jansen
A., Eickhoff S., Seubert J., Oddo S., Ermingen van M., Eberhardt K., Barthel J., Steiner F., Satrapi
P., Piskin A., Kobeleva X., Schwenke H., Yang H., Harders F., Chevreux A., Hoffstaedter F., Koch L.,
Theissen L., Arnolds K., Zvyagintsev M., Rath D., Becker H., Domahs F., Barthel J., Weyer D., Tonka
F., Eckers C., Koelzer F., Rueben M., Brieger J., Heinrich A., Hippmann K., Joue G.)
• Child and Adult Psychiatry
(Schulte-Ruether M., Seitz J., Bitar R., Altendorf S., Vogel K., Herten A., von Polier G., Dahmen B.,
Puetz V., Kuckartz L., Heimann P., Bubenzer S., Schmidt´T., Hueck M., Michel T.)
• Neurosurgery
(Fischer A., Skiba A., Kubina B., Ristic D., Matzeit K., Sevostianova N., Said Yekta S., Silke R., Gao Y.,
Jung K., Wego J., Hahn D.)
• Neurolinguistics
(Kamutzki D., Longoni F., Klann J., Wedler K., Kröger S., Grouls C., Ketteler D., Grande M., Tegtmeyer
M., Schulte S., Schindler A., Ketteler S., Bitzer R., Balthasar A., Seidel B., Etchevezry Saez L., da
Costa Avelar P., Schaeffner S., Helmbold K., Grebe C., Moormann M., Hillen R., Heller J.)
• Neurology
(Hütter D., Kastrau F., Meister I., Städtgen M., Schulte M., Sparing R., Boskojerdi B., Drews E., Foltys
H., Hesse M., Prange M., Wienemann M., Dambeck N., Etzold M., Alfaidy I., Chen H., Sakreida K.,
Ferrera Braja da Costa A., Nellessen N., Kleimann A., Helfrich R., Haarmeier T., Zizlsperger L., Sauvigny T., Pellicano A., )
• Neuropsychology
(Knops A., Spriestersbach A., Ruminska B., Schörner B., Klein E., Miessen E., Gamm F., Wood G.,
Krinzinger H., Heber I., Koten J., Kraus J., Spreckelmeyer K., Korvorst M., Pauly K., Winkler L., Beck
L., Boecker M., Thimm M., Graf M., Kob P., Vohn R., Feldmann R., Anders S., Lonnemann J., Geppert
B., Brandenburg D., Becher H., Nürk H.C., Galushko L., Reske M., Boge N., Schmenk B., Winters
T., Willmes K., Mainieri A., Patel H., Seifert A., Schlaegel S., Bay E., Tillmanns E., Henderichs J.,
Pohlhaus A., Dinkel P., Koehler F., Elkeles S., Gressnich J., Huetz D., Schumann B., Meyer E., Rath
C., Barzakova E., Meyer C., Schelenz P.D., Matteschk M.)
• Neuroradiology
(Winklhofer S., Blaum M., Stracke P., Krings T., Dammert S., Kränzlein H., Weidemann J., Niggemann
P., Albrecht J., Schmithausen J., Berthold-Losleben M.)
• Psychiatry, Psychotherapy and Psychosomatics
(Heindl A., Straube B., Klaerding C., Leube D., Schoth F., Rogge G., Thoennessen H., Vernaleken
I., Schnell K., Clos M., Schwenzer M., Qunaibi M., Weis S., Kellermann T., Daumann J., Lochner K.,
Holtkamp C., Fast K., Hollenborg N., Langner R., Fischermann T., Günther T., Niessen T., Zattarin
E., Sheldrick A., Halfter S., Irmak A., Marvani V., Kohn N., Finkelmeyer A., Pohl A., Dyck M., Kemper
C., Nagels A., Seidel E., Paulus F., Huebner A., Molnar B., Chechko N., Regenbogen C., Heim S.,
IZKF Aachen Progress Report 2011
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4.4.
Core Facilities
|
Brain Imaging Facility
Clemens B., Vieten A., Sahlmann M., Prempeh P., Herholz S., Mueller V., Pawliczek C., Mathiak K.,
Schock L., Schneider D., Gossen A., Palomero Gallagher N., Moessnang C., Schneider K., Kuijsten
W., Wojnar A., Cieslik E., Kellermann T., Groppe S.E., Chang C.Y., Scheller M., Kraemer J., Drexler
E., Demenescu L.R., Isman G.D., Reimers J., Brinkhaus M., Koczera P. Belke L., Kintzel F., Kirsch S.,
Sailee S., Farbood B., Vorhold V., Rao R., Oetken S., Fetz K., Wittenhagen L., Asensio S., Mathiak
K., Grodd W., Alawi E., Bhavsar S., Cordes J., Gaber T., Bath J., GroeneM., Semmler F., Kumar V.,
Gaebler A., Klasen M., Orfanos S., Piefke M., Arin T.)
Collaborations (with external partners or industrial partners)
• Clinical Science Group, Philips, Best, The Netherlands (Dr. Ruud de Boer)
• The Brain Innovation, Maastricht, The Netherlands (Goebel R., Heinecke A., Joost M.)
• RIKEN Brain Science, Japan (Nikolaev A.)
• University of Leuven, Belgium (Van Leeuwen C., Alexander D.)
• Department Head, Tomographic Imaging Systems at Philips Research in., Hamburg, Germany
(Dr. Dye Jensen)
• Zertrox GmbH & Co. KG, “Mess- und Steuerungstechnik“, Aachen, Germany (Vietzke K.)
• Brain Products, München, Germany (Svojanovsky E.)
• University of Freiburg, Germany (Zaitsev M.)
• Research Center Jülich, Germany (Shah J., Stöcker T.)
• Resonance Technology, USA (Ziarati M.)
Publications
IZKF relevant, project associated
1. Clemens, B., Zyvagintsev, M., Sack, A., Heinecke, A., Willmes, K., & Sturm, W. (2011).
Revealing the functional neuroanatomy of
intrinsic alertness using fMRI: methodological peculiarities. PLos one, 6 (9), e25453 [IF
4.411]
2. Dressel, K., Weiller, C., Huber, W., & Abel,
S. (2011). Gestörter Wortabruf im Modell
und im Gehirn. Eine Therapiestudie mit drei
Einzelfällen (Impaired word retrieval in a
cognitive model and in the brain. A therapy
study including three single cases). Sprache,
Stimme, Gehör, 35 (1), 19-25. [IF 0.111]
3. Jungblut M., Huber W., Pustelniak M.,
Schnitker R. (2011) Neuronale Korrelate
rhythmischer Strukturen beim Singen – eine
fMRT-Studie. Neurologie und Rehabilitation,
17 (1): p. 33-39. [IF 2.1996]
4. Jungblut M., Huber W., Pustelniak M., Schnitker R. (2011). The impact of rhythm complex-
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IZKF Aachen Progress Report 2011
5.
6.
7.
8.
ity on brain activation during simple singing
an event-related fMRI study. Restor.Neurol.
Neurosci., accepted ,DOI 10.3233/RNN-20110619. [IF 3.71]
Klasen M, Kenworthy CA, Mathiak KA,
Kircher TT, Mathiak K. (2011). Supramodal
Representation of Emotions. J Neurosci 2011;
31: 13635-13643 [IF 7.271]
Klasen M, Weber R, Kircher TT, Mathiak KA,
Mathiak K. (2011). Neural contributions to
flow experience during video game playing.
Soc Cogn Affect Neur.; doi: 10.1093/scan/
nsr021 [IF 4.482]
Koten JW Jr, Lonnemann J, Willmes K, Knops
A. Micro and macro pattern analyses of FMRI
data support both early and late interaction of
numerical and spatial information. Frontiers in
Human Neuroscience. 2011;5:115 [IF 1.94]
Schock, L., Schwenzer, M., Sturm, W., &
Mathiak, K. (2011). Alertness and Visuospatial
Core Facilities
Attention. BMC Psychiatry, 11, 3-8 [IF 2.891]
9. Sturm W., Schnitker R., Grande M., Huber
W., Willmes K. (2011): Common networks for
selective auditory attention for sounds and
|
Brain Imaging Facility
4.4.
words? An fMRI study with implications for
attention rehabilitation. Restorative Neurology
and Neuroscience, 29 (2011), p. 73–83. [IF
3.71]
IZKF Aachen Progress Report 2011
203
4.5.
Core Facilities
| Two-Photon Imaging Facility
Two-Photon Imaging Facility
Technical head of the facility:
Scientific head of the facility:
Scientific supervision:
Vogt M.
van Zandvoort M. (Institute for Molecular Cardiovascular Research)
Martin C. (Institute of Pharmacology and Toxicology)
Tolba R. (Institute of Laboratory Animal Science)
Services
Imaging techniques such as magnetic resonance
imaging, computer tomography, positron emission
spectroscopy, or ultrasound, enable non-invasive
visualization of various functional and structural
aspects of samples. However, the spatial resolution of these imaging modalities does not allow
visualization of subcellular structures. Moreover,
they sometimes lack the specificity that is required
for visualization of delicate molecular properties
of samples. These requirements are met by optical fluorescence microscopy which combines
subcellular resolution (< 1—m) with molecular
selectivity and sensitivity. However, with classical
fluorescence microscopic techniques, visualization of structures deep in intact viable samples
cannot be performed, even when using optical
techniques such as laser scanning confocal microscopy. Two-photon laser scanning microscopy (TPLSM) however, meets the requirements
for studying intact viable samples at subcellular
resolution. TPLSM is based on the principle of
two-photon excitation where simultaneous absorption of two near-infrared photons (total energy is equivalent to that of a single photon at half
the wavelength as used in classical fluorescence
microscopy) leads to the excited state of fluorescent molecules in the sample. Since two-photon
excitation only occurs in the focal position of the
microscope, out of focus absorption and excitation are absent. As a result, TPLSM possesses
enhanced depth penetration, good optical sectioning, and good resolution in three dimensions.
Moreover, photo-bleaching, photo-damage, and
photo-toxicity are reduced outside the area of
interest. The combination of all these features
makes TPLSM advantageous over other microscopic techniques for visualization of structures
located deeper in viable scattering or vulnerable
tissues in three dimensions.
204
IZKF Aachen Progress Report 2011
The two-photon core facility is equipped with two
modern two-photon laser scanning microscope
systems. A LaVision BioTec TrimScope two-photon microscope (2008) has a unique beam splitting device for simultaneous scanning of 64 foci
enabling fast image acquisition (up to 35Hz) in
a single channel up to a depth of 100—m in tissue (strongly dependent on type of sample) and
makes it is very well suited for in vivo imaging.
The second multiphoton system is an Olympus
Fluoview 1000 MPE (2009) and is the best choice
when maximal penetration depth (> 250—m deep
in atherosclerotic plaques, > 600—m in brain) is
required because of its highly efficient optics and
its powerful laser. Moreover, its flexible layout allows simultaneous detection of a wide range of
fluorescent molecules and easy adaptation to
various preparation methods.
Both systems can be used for in-vitro, ex-vivo,
in-situ, and in-vivo experiments and are mainly
prepared for imaging in rodents or isolated ‘whole
mount’ samples. Furthermore, we offer the option
for animal triggered in-vivo imaging, where ECG
and respiration signals are used to limit the impact of motional disturbances that occur due to
the heart- and respiration cycle on the imaging.
The latter triggering method enables studying of
structures prone to be shifted during in-vivo imaging.
In 2011, a motorized sample table was ordered
for the LaVision TrimScope. This enables the
simultaneous imaging of different areas in the
same sample for an effective study of time- and
cost-consuming experiments. Furthermore, the
fluorescence filter set was extended to offer more
flexibility in the imaging of fluorophores.
Core Facilities
| Two-Photon Imaging Facility
4.5.
Staff: ½ TV-L 14 (Vogt M.)
Materials/Travel expenses 2011: € 19,000
Investments/Equipment 2011: –
Revenues 2011: –
User
Users within the faculty
• Institute for Molecular Cardiovascular Research
(A. Schober: LPS1&3 contribution to neointima formation. / LacZ detection in Endothelium of various
mouse models. / Ministent project: test various coatings of stents.
R. Koenen: JAM-A expression in vitro and in viable healthy and atherosclerotic carotid arteries ex vivo.
M. van Zandvoort: Evaluation of multimodal contrast agents (fluoresence microbubbles; collaboration
with F. Kiessling) / Optimization of in vivo imaging methodology for studying atherosclerotic prone large
arteries.)
• Institute of Applied Medical Engineering
(S. Jockenhövel: Visualization of tissue engineered blood vessels.)
• Internal Medicine III
(F. Tacke, C. Martin: Migration and interaction of immune cells in liver tissue in vivo.)
• Pharmacology and Toxicology
(S. Uhlig / C. Martin: Calcium imaging in airway smooth muscle cells. / Nerves in vital lung tissue. /
Mechanostimulation (monoaxial and 3D stretching) of vital lung tissue (in collaboration with Prof. Wall,
LMU Munich). / Imaging of collagen and elastin in lung tissue by second harmonic generation)
• Dental Materials and Biomaterials Research
(H. Fischer: Feasibility tests detection of cell driven breakdown of dental (bio)materials.)
• Department of Plastic Surgery, Hand and Burns Surgery
(A. Bozkurt: Reconstruction of peripheral nerve defects with Schwann cell-seeded collagen scaffolds
with defined microstructure.)
• Department of Neuropathology
(G. Brook: Directional growth of neuronal cells on nanofibres incorporated into a 3D matrix.)
• Institute of Laboratory Animal Science
(B. Doorschodt: Assessment of FITC labeled Dextran distribution in kidney grafts during cold storage
and machine perfusion using Ecosol, a new preservation solution.)
• Department of Paediatric and Adolescent Medicine
(A. Schippers: Migration and interaction of cells in intestinal tissue in vivo.)
Collaborations (with external partners or industrial partners)
• Cardiovascular Research Institute, Maastricht University, the Netherlands
(M. van Zandvoort: Visualization of angiogenesis in atherosclerosis.)
• Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
(Weber C. / Megens R.: PMN recruitment atherosclerosis. / Monocyte recruitment atherosclerosis. /
Luminal chemokine deposition. / OxLDL uptake by neutrophils. / Transcytosis of granule proteins in the
endothelium.)
Publications
IZKF relevant, project associated
1. Soehnlein O, Wantha S, Simsekyilmaz S,
Döring Y, Megens RT, Mause SF, Drechsler
M, Smeets R, Weinandy S, Schreiber F, Gries
T, Jockenhoevel S, Möller M, Vijayan S, van
Zandvoort MA, Agerberth B, Pham CT, Gallo
RL, Hackeng TM, Liehn EA, Zernecke A, Klee
D, Weber C (2011)
Neutrophil-derived cathelicidin protects from
neointimal hyperplasia.
Sci Transl Med. 3(103):103ra98. (Impact
3.511)
IZKF Aachen Progress Report 2011
205
4.5.
Core Facilities
| Two-Photon Imaging Facility
2. Weber C, Meiler S, Döring Y, Koch M,
Drechsler M, Megens RT, Rowinska Z,
Bidzhekov K, Fecher C, Ribechini E, van
Zandvoort MA, Binder CJ, Jelinek I, Hristov
M, Boon L, Jung S, Korn T, Lutz MB, Förster
I, Zenke M, Hieronymus T, Junt T, Zernecke A
(2011)
CCL17-expressing dendritic cells drive
atherosclerosis by restraining regulatory T cell
homeostasis in mice.
J Clin Invest. 121(7): 2898–2910. (Impact
14.152)
3. Zhou Z, Subramanian P, Sevilmis G, Globke
B, Soehnlein O, Karshovska E, Megens R,
Heyll K, Chun J, Saulnier-Blache JS, Reinholz
M, van Zandvoort M, Weber C, Schober A
(2011)
Lipoprotein-Derived Lysophosphatidic Acid
Promotes Atherosclerosis by Releasing
CXCL1 from the Endothelium.
Cell Metab. 13(5):592-600. (Impact 18.207)
4. Megens RT, Kemmerich K, Pyta J, Weber C,
Soehnlein O (2011)
Intravital imaging of phagocyte recruitment.
Thromb Haemost. 105(5):802-10. (Impact
4.701)
Applied and current third-party funding
(DFG, BMBF, EU, foundations)
Van Zandvoort,
M.
206
IZKF Aachen Progress Report 2011
Grant Two-Photon Microscopy
DFG
359903
01/201112/2011
€ 25,000
Core Facilities
| Transgenic Service
4.6.
Staff: TV-L 9 (Tropartz T.)
TV-L 5 (Siebert F.)
½ TV-L 14 (Vogt M.)
Materials/Travel expenses 2011: € 800
Investments/Equipment 2011: € 3,094
Revenues 2011: –
Transgenic Service
Technical head of the facility:
Scientific supervision:
Tropartz T.
Tolba R. (Institute of Laboratory Animal Science)
Services
The “Transgenic Service” (TGS) supports all academic faculty members at the University Hospital
ofRWTH Aachen as well as RWTH Aachen University with the generation of genetically modified (transgenic or knock-out) mouse strains.
Thereby, cloned DNA sequences are transferred
into the genome of the animals. Depending on
the scientific aim the inserted DNA sequence is
translated into a biologically active protein or a
certain gene of the recipient animal is modified
or knocked out. For the generation of genetically
modified mice (e.g. as model systems for investigation of human diseases) predominantly two
methods are used:
Pronucleus injection: Transgenic DNA constructs
are injected in the pronucleus of fertilized eggs.
These DNA constructs can contain species-specific or foreign genes under control of speciesspecific or foreign promoters. The transgenic
embryos are transferred into pseudopregnant
recipient mice. A part of the newborn mice has
integrated this transgene into the host genome.
These founders are then used as source animals
for subsequent transgenic breeding to establish
a line.
Homologe recombination (HR): Embryonic murine stem cells containing the target gene which
was knocked down by HR are injected into mouse
embryos (blastocysts). Cells with the knock-out
allele can contribute to the formation of the germline. Thus, mice with mutations in specific genes
can be generated (e. g. „knock-out“ mice) who
can pass those mutations to the offspring. The
observed defects in mice containing knock-out
mutations allow conclusions to be drawn about
the biological function of the targeted gene.
Moreover, the transgenic service is responsible
for the cryo-preservation and archiving of mouse
strains by mating hormone treated wild type donor females with the matching donor males. The
embryos are isolated and handled in special
media and are frozen by the low-rapid freezing
method in a propylene glycol medium. The embryos are cooled down by a decrease in temperature of 0.3 – 0.8°C / min to -30°C and afterwards
transferred into liquid nitrogen (-196 °C) for long
time storage.
The slow freezing process reduces the crystallization inside the embryos and thereby increasing
the survival rate during thawing.
The cryo-preservation of mice strains strongly
minimizes the health risk for animal facilities and
reduces the animal housing costs for the users.
Furthermore, instead of living animals, frozen
embryos can be shipped to other institutes on
demand, avoiding an expensive rederivation in
order to transfer animals in their breeding areas.
Cryo-preserved embryos are implanted in pseudo-pregnant mice and are delivered by these
foster mice.
Another main focus of our service unit is the rederivation of mouse strains by performing embryo transfers for hygienic or strain-conservation
reasons. Therefore, hormone stimulated donor
females are mated with matching donor males in
our quarantine area. Embryos are retrieved from
the oviduct of the donor females and are implanted into pseudo-pregnant foster mice. Offspring
are characterized by genotyping and foster mice
are examined for hygienic screening according
to the FELASA guidelines in our microbiological
laboratory.
Since last year the facility offers in-vitro fertilization (IVF) as an additional service. This method
consists of sperm extraction from the vas deferens and cauda epididymis of a male donor
mouse. The sperms are incubated with matching
oocytes of donor females in special medium over
several hours. The fertilized eggs can develop to
the blastocyst stage in the incubator or the eggs
are implanted in a pseudo-pregnant female.
In 2011, the transgenic service unit has coun-
IZKF Aachen Progress Report 2011
207
4.6.
Core Facilities
| Transgenic Service
seled numerous working groups about different
services. Because of the diversity of these consultations no detailed listing is shown.
Services performed in 2011:
Rederivation of mouse strains
Generation of knock-out / knock-in mice
Generation of transgenic mice
Cryo-preservation of mouse strains
Revitalization
In-vitro fertilizationen
Ms. Siebert and Ms. Tropartz visited the 49th
scientific meeting of the GV-SOLAS (Society of
Laboratory Animal Science) in Dresden.
25
4
3
16
4
1
(Services not completed in 2011 are not listed)
To maintain the hygiene standard in our SPF animal housing, 72 health controls were ordered by the transgenic core facility. Resulting costs including equipment maintenance, investments etc. could be covered by
incmings from the services.
208
Material costs:
Animal housing costs:
Investments:
Health control costs:
€ 6,905,17
€ 21,487,79
€ 6,372,34
€ 6,765,12
Sum total:
€ 41,530,42
IZKF Aachen Progress Report 2011
Transfer from 2010:
Revenues 2011:
€ 5,852,11
€ 38,580,11
Total sum:
€ 44,432,24
Transfer to 2012:
€ 2,901,82
| Transgenic Service
4.6.
IZKF Aachen Progress Report 2011
209
Core Facilities
User
Users within the faculty
• Department of Paediatric and Adolescent Medicine
(Prof. Dr. Wagner, Dr. Schippers, Dr. Tenbrock, Honke N.)
• Department of Anatomy (Prof. Dr. Leube, Kant S., Creutz V., Dr. Schwarz, Dr. Krusche)
• Internal Medicine III
(Prof. Dr. Trautwein, Dr. Lüdde, Dr. Tacke, Dr. Liedtke, Dr. Streetz, Koppe C., Kreggenwinkel K.,
Dr. Sackett, Dr. Sellge)
• Institute of Biomedical Engineering, Cell Biology (Prof. Dr. Zenke, Dr. Sechi, Dr. Hieronymus)
• Institute of Biochemistry and Molecular Biology (Prof. Dr. Lüscher, Prof. Dr. Bernhagen, Dr.
Lüscher-Firzlaff , Ullius A., Lennartz B., Hoch B.)
• Internal Medicine II
(PD Dr. med. Möller, Tenten V., Prof. Dr. Ostendorf, Dr. van Roeyen, Martin I., Dr. Kunter,
Frau Stüttgen)
• Institute for Molecular and Cardiovascular Research (Prof. Dr. Schober)
• Department of Anatomy (Prof. Dr. Pufe, Dr. Wruck, Dr. Brandenburg)
• Department of Neuropathology (Prof. Dr. Weis, Katjna I., Dr. Nachreiner)
• Institute of Clinical Chemistry and Pathobiochemistry (Prof. Dr. Weiskirchen)
• Institute for Biomedical Engineering - Biointerface Laboratory
(Prof. Dr. Jahnen-Dechent, Dietzel E.)
• Institute of Pharmacology and Toxicology (Dr. Martin, Dr. Dreymüller)
• Internal Medicine IV (Dr. Ziegler)
• Department of Vascular Surgery (Dr. Kokozidou, Rowinska Z.)
• Department of Neurology (Prof. Dr. Schulz, Dr. Reich)
• Institute of Physiology (Prof. Dr. Gründer, Dr. Wiemuth, Dr. Schnizler)
External user
• Institute of Biology II, Zoology - Cellular Neurobionic, RWTH Aachen
(Prof. Dr. Baumgartner, Dolge L.)
Collaborations (with external partners or industrial partners)
• University Maastricht (Frijnts R.)
• Helmholtz-Institute for Biomedical Engineering (Lunze K.)
FUNDING
p. 212
PA R T I C I PAT I N G I N S T I T U T E S A N D C L I N I C S
p. 216
O U T P U T A N D E VA L U AT I O N
p. 219
STRUCTURE AND RESPONSIBILITIES
p. 220
ANNUAL REPORT
In 2011, the IZKF received € 3,175,380 from the State Grant for
Research and Teaching, as fixed in the faculty budget. It also
received a faculty grant of € 1,124,620. With reserves of € 260,613
for 2010, the IZKF had a total budget of € 4,560,613.
5.1.
Annual Report
|
Funding
Funding
During the report period 4,199,206 Euro or 93 percent of the total budget was spent. Therefore reserves in the amount of
67,166 Euro were set aside.
212
IZKF Aachen Progress Report 2011
Annual Report
|
Funding
5.1.
Of the total expenses in 2011, amounting to 4,199,206, 44 Euro percent was spent on project funding, 22 percent on funding
young researchers and 26 percent on core facilities and the core laboratory. A further 8 percent was spent on the administration
office and central costs, such as travel funds, job advertisements and costs for events.
1,825,579 Euro was spent on project funding. The four research focus area of the IZKF correspond to those of the Faculty of
Medicine of the RWTH: Medicine and Technology, Cardiovascular Research, Clinical Neurosciences and Inflammation and
Consequences.
IZKF Aachen Progress Report 2011
213
5.1.
Annual Report
|
Funding
916,443 Euro was spent on funding young researcher. The program “Junior Research Projects“ started in 2008. In 2011, twelve
junior researchers worked on a junior project, associated with IZKF funded research projects. The program ended in 2011 and
will not be pursued. The Young Reseacher Groups of Prof. Thumann und Prof. Ludwig will be funded until 2012. In summer
2012, the funding of 4 new Researcher Groups will start.
Core Facilities and the Core Laboratory were funded with 1,107,488 Euro in total. The Brain Imaging Facility and the Chip Facility are solely IZKF Core Facilities. The Immunohistochemistry and Confocal Laser Scanning Microscopy Facility is supported
by the Institute of Biochemistry and the IZKF. The Two-Photon Imaging Facility and the Transgenic Service is also supported
by the Faculty of Medicine. The Chair of the IZKF decided to stop the funding of the Mice Echocardiography Facility and only
disbursed the maintenance contract of the equipment (1,111 Euro). The IZKF supported the proposal for a “Biomaterial Bank”,
an initiative of the Federal Ministry of Education and Research by funding personnel (48,163 Euro). The proposal was granted
and the Biomaterial Bank was established in 2011.
214
IZKF Aachen Progress Report 2011
Annual Report
|
Funding
5.1.
IZKF Aachen Progress Report 2011
215
Financial Overview 2011
Total Budget
€ 4,560,613
Expenses
€ 4,199,206
Sum of Project Funding
€ 1,825,579
focus area 1: Medicine and Technology
€ 261,511
focus area 2: Cardiovascular Research
€ 394,438
focus area 3: Clinical Neurosciences
€ 651,218
focus area 4: Inflammation and Consequences
€ 518,412
Sum of Funding Young Researchers
€ 916,443
Young Researcher Groups
€ 556,575
Junior Research Projects
€ 354,657
Rotation Programm
Sum of Core Facilities
€ 5,212
€ 1,107,488
Chip Facility
€ 208,016
Immunohistochemistry and CLSM Facility
€ 202,242
Brain Imaging Facility
€ 485,163
Transgenic Service
€ 112,461
Two-Photon Imaging Facility
Proteomics Facility
Biobank
Mice Echocardiography
€ 47,648
€ 2,685
€ 48,163
€ 1,111
Administration Office and Central Costs*
€ 349,695
Reserves
€ 361,407
transferable project-bounded funds
€ 294,241
transferable non-project-bounded funds
€ 67,166
*Core Laboratory, Investment Pool, Job Advertisements, Travel Funds, Prize Money
5.2.
Annual Report
|
Participating Institutes and Clinics
Participating Institutes and Clinics
Central Services
Institute of Transfusion Medicine
Institute of Laboratory Animal Science
Clinical Departments
Department of Anaesthesiology
Department of Cardiology, Pneumology, Angiology and Internal Medicine Intensive Care
(Internal Medicine I)
Department of Cardiac and Thorax Surgery
Teaching and Research Area Child Cardiac Surgery
Department of Child and Adolescent Psychiatry and Psychotherapy
Teaching and Research Area Clinical Child and Adolescent Neuropsychology
Department of Dental Preservation
Teaching and Research Area Oral Microbiology and Immunology
Department of Dermatology
Department of Diagnostic and Interventional Radiology
Department of Diagnostic and Interventional Neuroradiology
Department of Gynaecology and Obstetrics
Teaching and Research Area Prenatal Medicine
Department of Gynaecological Endocrinology and Reproductive Medicine
Department of Neurosurgery
Department of Neurology
Teaching and Research Area Clinical Cognition
Teaching and Research Area Neuropsychology
Department of Nuclear Medicine
Department of Ophthalmology
Teaching and Research Area Experimental Ophthalmology
Department of Orthodontics
Department of Orthopaedics and Trauma Surgery, main focus on orthopaedics
Department of Orthopaedics and Trauma Surgery, main focus on trauma surgery
Department of Otorhinolaryngology and Plastic Head and Neck Surgery
Department of Paediatric and Adolescent Medicine
Teaching and Research Area Neonatological Intensive Care
Department of Paediatric Cardiology
Department of Palliative Medicine
Department of Phoniatrics, Pedaudiology and Communication Disorders
Department of Plastic, Hand and Burns Surgery
216
IZKF Aachen Progress Report 2011
–
X
–
X
–
–
X
X
–
–
–
–
X
–
–
–
–
X
–
X
–
X
X
–
–
–
–
X
–
–
–
–
–
Annual Report
Department of Prosthodontics and Dental Materials
Teaching and Research Area Dental Materials and Biomaterials Research
Department of Psychiatry, Psychotherapy and Psychosomatics
Teaching and Research Area Experimental Neuropsychiatry
Teaching and Research Area Psychopathology
Teaching and Research Area Experimental Behavioral Psychobiology
Teaching and Research Area Structural Functional Brain Mapping
Teaching and Research Area Structure of Cortical Functional Units
Teaching and Research Area Functionality of Cortical Circuits
Teaching and Research Area Neuropsychological Gender Studies
Department of Oral Maxillofacial and Plastic Facial Surgery
Department of Radiotherapy
Department of Surgery
Department of Urology
Department of Vascular Surgery
Internal Medicine II (Nephrology and Clinical Immunology)
Internal Medicine III (Gastroenterology and Metabolic Disorders)
Internal Medicine IV (Haematology and Oncology)
Surgical Intensive Care
Institutes
Institute of Aerospace Medicine
Institute of Anatomy and Cell Biology
Institute of Biochemistry and Molecular Biology
Institute of Biochemistry and Molecular Cell Biology
Teaching and Research Area Biochemistry and Molecular Immunology
Helmholtz-Institute for Biomedical Engineering (Applied Medical Engineering)
Teaching and Research Area Rehabilitation and Prevention Engineering
Teaching and Research Area Cardiovascular Engineering
Teaching and Research Area Tissue Engineering and Textile Implants
Helmholtz-Institute for Biomedical Engineering (Experimental Molecular Imaging)
Helmholtz-Institute for Biomedical Engineering (Cell Biology)
Teaching and Research Area Stem Cell Biology
Helmholtz-Institute for Biomedical Engineering (Biointerface)
Institute of Clinical Chemistry and Pathobiochemistry
Teaching and Research Area Molecular Pathobiochemistry
and Experimental Gene Therapy
Institute of History, Theory and Ethics in Medicine
Institute of Human Genetics
Institute for Hygiene and Environmental Medicine
Institute of Immunology
|
Participating Institutes and Clinics
5.2.
X
X
X
–
X
X
–
–
–
X
–
–
–
–
–
X
X
–
X
–
X
X
X
X
X
–
–
X
X
X
–
–
X
X
–
X
–
–
IZKF Aachen Progress Report 2011
217
5.2.
Annual Report
|
Participating Institutes and Clinics
Institute of Medical Psychology und Medical Sociology
Institute of Medical Informatics
Institute of Medical Statistics
Institute of Medical Microbiology
Teaching and Research Area Virology
Institute of Molecular and Cellular Anatomy
Institute for Molecular Cardiovascular Research
Teaching and Research Area Cardiovascular Biochemistry
Institute of Neuroanatomy
Institute of Neuropathology
Institute and Out-patient Clinic of Occupational Medicine
Institute of Pharmacology and Toxicology
Teaching and Research Area Pharmacology
Teaching and Research Area Pharmacology of Inflammation
Institute of Pathology
Teaching and Research Area Tumour Pathology
Institute of Physiology
Teaching and Research Area Cardiovascular Physiology
In the following graphic the participation of clinics and institutes in IZKF projects is illustrated:
218
IZKF Aachen Progress Report 2011
X
–
–
–
–
X
X
X
X
X
–
X
–
X
X
–
X
–
Annual Report
|
Output and Evaluation
5.3.
Output and Evaluation
The following table gives an overview of the
achievements of the IZKF during the last 16
years. Details about the different parameters, as
Parameter
Publications*
Scientific degrees**
Appointments
Form
Articles
Diploma theses
Doctoral theses
Postdoctoral
Lecture Qualification
well as titles of theses and publications can be
found in the project report.
1996-2006
303
38
64
18
2007
60
6
5
2
2008
81
3
12
0
2009
49
7
9
3
2010
61
10
9
4
2011
101
15
15
3
u.f.
6
6
7
8
2
* IZKF support must be mentioned in publications and presentations Publications are relevant to the IZKF
if the support is mentioned in the acknowledgement and/or in the affiliation.
The number of publications fluctuates year to year and depends on which stage the project is in during the
funding period. The number of publications is higher in 2011 than in 2010 because in 2011 a three-year
funding periodended. The current funding period will end in 2014.
** Information about diploma theses and doctoral theses can be found in the project reports.
IZKF Aachen Progress Report 2011
219
5.4.
Annual Report
|
Structure and Responsibilities
Structure and Responsibilities
The organs of the IZKF Aachen as per the constitution are the Chair, the External Research Advisory Board
and the General Assembly. The structure of the IZKF is outlined in the following diagram:
220
IZKF Aachen Progress Report 2011
Annual Report
|
Structure and Responsibilities
5.4.
Chair
The Chair of the IZKF is elected by the heads
of the funded projects for a term of three years.
The Chair carries the total responsibility for the
IZKF, manages the affairs, as long as they are
not part of the operational day-to-day business.
The research coordinator is responsible for the
administration business according to prior agreement with the Chair in connection with the financial management of the university clinic.
The Chair during report period consisted of following members:
Speaker
Prof. Dr. Peter Walter
Department of Ophthalmology
Representative
Speaker
Prof. Dr. Bernhard Lüscher
Institute of Biochemistry and Molecular Biology
Representative
of Engineering
Sciences
Prof. Dr. Thomas Gries
Institute of Textile Technology
Coordinators of the Prof. Dr. Martin Zenke
research focus areas Prof. Dr. Andreas Schober
Prof. Dr. Klaus Willmes
PD Dr. Frank Tacke
Institute of Biomedical Engineering – Cell Biology
Institute for Molecular Cardiovascular Research
Department of Neurology, Section Neuropsychology
Department of Medicine III
Prof. Dr. Stefan Jockenhövel
Representative
Coordinators of the Prof. Dr. Jürgen Bernhagen
research focus areas Prof. Dr. Joachim Weis
Prof. Dr. Tammo Ostendorf
AME – Institute
Institute of Biochemistry and Molecular Cell Biology
Department of Neuropathology
Department of Medicine II
Heads of
the Junior
Research Groups
Prof. Dr. Andreas Ludwig
Prof. Dr. Gabriele Thumann
Institute of Pharmacology and Toxicology
Department of Ophthalmology
Advisory members
Prof. Dr. Stefan Uhlig
Prof. Dr. Jürgen Floege
Prof. Dr. Frank Schneider
(represented by Prof. Dr. Ute Habel)
Prof. Dr Christian Trautwein
Dean of the Faculty of Medicine
Dean for Research and Funding of Young Researchers
Speaker of the IRTG 1328 Schizophrenia and Autism
Karen De Bruyne M.A.
Research Coordinator of the IZKF
Guest
Speaker of the Collaborative Research Center TRR 57
IZKF Aachen Progress Report 2011
221
5.4.
Annual Report
|
Structure and Responsibilities
External Research Advisory Board
The External Research Advisory Board consists
of experienced experts and represents the research focus areas of the IZKF, which have corresponded to the research focus areas of the
Faculty of Medicine since 2009. The External
Research Advisory Board inspects the concept
of the research focus areas, the projects and the
scientific and structural development of the IZKF.
It reviews the proposals and gives clear funding
recommendations or refusals. Refusals of the
External Research Advisory Board are binding.
Recommendations should take effect if financially possible.
The following experts are members
of the External Research Advisory Board:
Chairman of the External
Research Advisory Board
Prof. Dr. Georg Peters
University Hospital Muenster Domagkstraße 10
Institute of Medical
48149 Muenster
Microbiology
Phone:+49 251 8355360
[email protected]
Research Focus Area 1: Medicine and Technology
Prof. Dr. Jürgen Hescheler
University Cologne Faculty
of Medicine - Institute of
Neurophysiology
Prof. Dr. Klaus Jandt
University of Jena
Löbdergraben 32
Institute of Materials Science 07743 Jena
and Technology (IMT)
Phone:+49 3641 9477-30
[email protected]
Prof. Dr. Wolfram-Hubertus University of Göttingen
Department Pharmacology
Zimmermann
222
Robert-Koch-Strasse 39
50931 Cologne
Phone:+49 221 4786960
[email protected]
Robert-Koch-Str. 40
37075 Göttingen
Phone: +49 551 39-5781
[email protected]
Prof. Dr. med. Dr. rer. nat.
Wolfhard Semmler
German Cancer
Research Center
Department of Medical
Physics with Distinction
in Radiotherapy and
Biomedical Optics
Prof. Dr. Katrin Sternberg
University of Rostock Institute Friedrich-Barnewitz-Straße 4
of Biomedical Engineering
18119 Rostock
Department Biomaterials
Phone:+49 381 54345-525
[email protected]
IZKF Aachen Progress Report 2011
Im Neuenheimer Feld 280
69120 Heidelberg
Phone: +49 6221 42 2550
[email protected]
Annual Report
|
Structure and Responsibilities
5.4.
Further experts:
Prof. Dr. med.
Wolfgang-Michael Franz
University Hospital Munich
Internal Medicine I
Marchioninistraße 15
81377 München
Phone: +49 89 7095 6095
[email protected]
Prof. Dr.-Ing. Jörg Vienken
Fresenius Medical Care
Germany GmbH
61352 Bad Homburg
Phone: +49 6172 6090
[email protected]
Prof. Dr. rer. nat.
Bernhard Wolf
Technical University
of Munich (TUM)
Heinz Nixdorf-Chair in
Medical Elektronics
Theresienstraße 90 / N3
80333 München
Phone: +49 89 / 289 22947
[email protected]
Research Focus Area 2: Cardiovascular Research
Prof. Dr. Dr. Gerd Heusch
University of Essen
Center of Internal Medicine
Institute of Pathophysiology
Hufelandstrasse 55
45122 Essen
Phone: +49 201 7234480
[email protected]
Prof. Dr. Mat Daemen
University of Maastricht
CARIM
P.O. Box 616
6200 MD Maastricht
Phone: +49 31 43 3881766
[email protected]
Prof. Dr.
Bernhard Nieswandt
University of Würzburg
DFG-Research Center for
Experimental Biomedicine
Josef-Schneider-Straße 2, Haus D15
97080 Würzburg
Phone: +49 931 31 80406
[email protected]
uni-wuerzburg.de
Prof. Dr. Klaus Preissner
University of Giessen
Institute of Biochemistry
Friedrichstr. 24
35392 Giessen
Phone:+49 641 99 47501
[email protected]
uni-giessen.de
Prof. Dr. med.
Ingrid Fleming
Goethe University
Center for Molecular
Medicine
ECCPS Chair for
Vascular Signalling
Theodor-Stern Kai 7
60596 Frankfurt/Main
Phone:+49 69 6301 6972 [email protected]
vrc.uni-frankfurt.de
IZKF Aachen Progress Report 2011
223
5.4.
Annual Report
|
Structure and Responsibilities
Further experts:
Prof. Dr. Daniel Teupser
University Hospital
Leipzig AöR
Institute of Laboratory
Medicine, Clinical Chemistry
and Molecular Diagnostics
Liebigstraße 27
04103 Leipzig
Phone: +49 341 9722204
[email protected]
Prof. Dr. Dr.
Stefan Engelhardt
Technical University of Munich (TUM)
Institute of Pharmacology
and Toxicology
Biedersteiner Str. 29
80802 Munich
Phone: +49 89 4140-3260
[email protected]
Prof. Dr. Christoph Bode
University Hospital Freiburg
Internal Medicine III
Hugstetterstr. 55
79106 Freiburg
Phone: +49 761 27034 41
[email protected]
Research Focus Area 3: Clinical Neurosciences
224
Prof. Dr. med.
Bernhard Blanz
Friedrich-SchillerUniversity of Jena
Department of Child and
Adolescent Psychiatry
Philosophenweg 3/5
07743 Jena
Phone: +49 3641 936581
[email protected]
Prof. Dr. Peter Falkai
Georg-August-University
of Göttingen
Department of Psychiatry
and Psychotherapy
von-Siebold-Str. 5
37075 Göttingen
Phone: +49 551 396601
[email protected]
Prof. Dr. med. Heinrich
Sauer
Friedrich-Schiller-University
of Jena
Department of Psychiatry
and Psychotherapy
Philosophenweg 3
07743 Jena
Phone: +49 3641 935242
[email protected]
Prof. Dr.
Albert Christian Ludolph
University Hospital Ulm
Department of Neurology
Oberer Eselsberg 45
89081 Ulm
Phone: +49 7311771200
[email protected]
Prof. Dr. Peter Young
University Hospital Muenster Albert-Schweitzer-Str. 33
Department of Neurology
48129 Muenster
Phone: +49 251 8348331
[email protected]
IZKF Aachen Progress Report 2011
Annual Report
|
Structure and Responsibilities
5.4.
Further experts:
Prof. Dr. Ulrich Bogdahn
University Hospital
Regensburg
Policlinic of Neurology
Universitätsstraße 84
93053 Regensburg
Phone: +49 941 941 3001
[email protected]
Prof. Marianne Dieterich
University Hospital Munich
Department of Neurology
Marchioninistr. 15
81377 München
Phone: +40 89 7095 2571
[email protected]
Prof. Dr. Karl-Heinz Plate
Johann Wolfgang
Goethe-University
Institute für Neuropathology
Heinrich-Hoffmann-Straße 7
60528 Frankfurt am Main
Phone: +49 69 6301 6042
[email protected]
Research Focus Area 4: Inflammation and Consequences
Ismaninger Straße 22
Prof. Dr. Roland M. Schmid Technical University
of Munich (TUM)
81675 Munich
Medical Clinic II und Policlinic Phone: +49 89 41402251
[email protected]
Prof. Dr. Gisa Tiegs
University Hospital
Hamburg-Eppendorf
Center for Internal Medicine
Prof. Dr. Kai-Uwe Eckardt
University Hospital Erlangen
Internal Medicine IV
Prof. Dr. Thomas Benzing
University Hospital Cologne
Nephrology und General
Internal Medicine
Kerpener Str. 62
50937 Cologne
Phone: +49 221 4784480
thomas.benz[email protected]
Prof. Dr. med.
Norbert Weiler
University Hospital
Campus Kiel
Department of
Anaesthesiology and
Surgical Intensive Care
Schwanenweg 21
24105 Kiel
Phone: +49 431 5972991
[email protected]
Martinistraße 52
20246 Hamburg
Phone:+49 40 741058731
[email protected]
Krankenhausstrasse 12
91054 Erlangen
Phone: +49 9131 8539002
[email protected] &
University Hospital Nürnberg Breslauer Straße 201
90471 Nürnberg
Phone: +49 911 3982702
[email protected]
IZKF Aachen Progress Report 2011
225
5.4.
Annual Report
|
Structure and Responsibilities
Further experts:
Prof. Dr. med.
Stefan Bischoff
University of Hohenheim
Institute of Nutritional
Medicine
Fruwirthstr. 12
70599 Stuttgart
Phone: +49 711 45924100
[email protected]
Prof. Dr.
Karl Lenhard Rudolph
University of Ulm
Institute of Molecular
Medicine and
Max-Planck-Research-Group
for Stem Cells Ageing
Albert-Einstein-Allee 11
89081 Ulm
Phone: +49 731 5036101
[email protected]
Prof. Dr. Dr. Thomas Thum Medical University
of Hannover
IFB, Molecular and
Translational
Therapystrategies
Carl-Neuberg-Str. 1
30625 Hannover
Phone: +49 511 5325272
[email protected]
General Assembly
According to the new statutes the General Assembly consists of the responsible heads of the
projects, the core facilities and the researcher
groups. An associated membership can be ap-
plied for by IZKF financed scientists and important cooperation partners of the IZKF funded
projects.
Members of the General Assembly
Bernhagen, Jürgen
Beyer, Cordian
Burgmaier, Mathias
Denecke, Bernd
Ensslen, Silke
Falkenburger, Björn
Fischer, Horst
Gauggel, Siegfried
Gründer, Stefan
Günther, Erdenechimeg
Habel, Ute
Huber, Walter
Huber, Michael
226
IZKF Aachen Progress Report 2011
Jockenhövel, Stefan
Kiessling, Fabian
Koenen, Robert Ryan
Konrad, Kerstin
Leube, Rudolf
Liehn, Elisa-Anamaria
Ludwig, Andreas
Lüscher, Bernhard
Mathiak, Klaus
Mingoia, Gianluca
Möller, Marcus
Mottaghy, Felix M.
Müller-Newen, Gerhard
Noels, Heidi
Ostareck-Lederer, Antje
Ostendorf, Tammo
Preisinger, Christian
Pufe, Thomas
Rudnik-Schöneborn, Sabine
Schnitker, Ralph
Schober, Andreas
Sechi, Antonio S.
Senderek, Jan
Streetz, Konrad
Suschek, Christoph
Tacke, Frank
Annual Report
Tenbrock, Klaus
Trautwein, Christian
Thumann, Gabriele
Tolba, René
Uhlig, Stefan
Vervoorts-Weber, Jörg
Vogt, Felix
Vogt, Michael
Weiskirchen, Ralf
Wiesmann, Martin
Wasmuth, Hermann E.
Weis, Joachim
In total there were 79 IZKF members in
2011:
|
Structure and Responsibilities
5.4.
Willmes, Klaus
Zenke, Martin
Zerres, Klaus
Zvyagintsev, Mikhail
Participation of men and women
Speaker:
1
Heads of the Junior
Research Groups:
2
Heads of the Core Facilities:
9
Junior Researcher:
11
Co-Heads of funded projects:
44
Responsible Heads
of funded projects:
11
Specialization of the IZKF members
IZKF Aachen Progress Report 2011
227
228
IZKF Aachen Progress Report 2011
P U B L I C AT I O N S 2 0 11
6.
Publications 2011
Publication list 2011
of IZKF relevant publications
230
Authors
Title
Auer-Grumbach M., Weger M.,
Fink-Puches R., Papić L., Fröhlich E.,
Auer-Grumbach P., El Shabrawi-Caelen
L., Schabhüttl M., Windpassinger C.,
Senderek J., Budka H., Trajanoski S.,
Janecke A.R., Haas A., Metze D.,
Pieber T.R., Guelly C.
Fibulin-5 mutations link
Brain 134:1839-52. [IF 9,23]
inherited neuropathies, agerelated macular degeneration
and hyperelastic skin
Arnold S., Viktor M.B., Beyer C.
Estrogen and the regulation
of mitochondrial structure
and function
Bach C., Jockenhövel S., Gries T.
Produkt-, Prozess- und
Technik-Magazin von
Maschinenentwicklung in der Landesverband NRW des
textilen Medizintechnik Tec2 VDI, Aachener und Kölner
BV 126
Bergmann C., Weiskirchen R.
J Hepatol Nov 28. [Epub
It’s not all in the cilium,
ahead of print] [IF 9.334]
but on the road to it:
Genetic interaction network
in polycystic kidney and liver
diseases and how trafficking
and quality control matter
Borkham-Kamphorst E., Drews F.,
Weiskirchen R.
Induction of lipocalin-2
expression in acute and
chronic experimental liver
injury moderated by proinflammatory cytokines
interleukin-1` through
nuclear factor-gB activation
Liver Int 31:656-665 [IF 2.99]
Borkham-Kamphorst E.,
Zimmermann H.W., Karlmark K.R.,
Van de Leur E., Bauer J., Tacke F.,
Weiskirchen R.
Lipocalin-2 (LCN2) in
experimental liver injury and
human liver diseases
Z Gastroenterol 49: 88
[Abstract]
Boyalla S., Victor M.B., Roemgens A.,
Beyer C., Arnold S.
Sex- and brain regionspecific role of cytochrome
c oxidase in 1-methyl-4phenylpyridinium-mediated
astrocyte vulnerability
J Neurosci Res 89:20682082 [IF 2.9]
Clemens B., Zvyagintsev M., Sack A.,
Heinecke A., Willmes K., Sturm W.
Revealing the Functional
Neuroanatomy of Intrinsic
Alertness Using fMRI:
Methodological Peculiarities
PLoS ONE 6(9):
e25453. doi:
10.1371/journal.
pone.0025453 [IF 4.411]
IZKF Aachen Progress Report 2011
Medium
J Steroid Biochem Mol Biol
in press [IF 2.9]
Publications 2011
6.
IZKF Aachen Progress Report 2011
231
Authors
Titel
Medium
Ding, X., Lin, Q., Ensenat-Waser, R.,
Rose-John, S. and Zenke, M.
Polycomb group protein Bmi1 Stem Cells Dev. 21, 121-132
promotes hematopoietic cell [IF 4.791]
development from ES cells
Do O. N.T., Eurich D., Schmitz P.,
Schmeding M., Heidenhain C., Bahra C.,
Trautwein C., Neuhaus P.,
Neumann U.P., Wasmuth H.E.
A seven gene signature of
Liver Transpl, in press
the recipient predicts pro[IF 3.07]
gression of fibrosis after liver
transplantation for hepatitis C
infection
Domahs F., Nagels A., Domahs U.,
Whitney C., Wiese R., Kircher T.
Where the mass counts:
Common cortical activation
for different kinds of nonsingularity.
Journal of Cognitive
Neuroscience [IF 5.357]
Döring, Y.*, Soehnlein, O.*,
Drechsler, M., Meiler, S.,
Shagdarsuren, E., Hartwig, H.,
Hieronymus, T., Hristov, M.,
Koenen, R.R., Zenke, M., Weber, C.,
Zernecke, A.
Chronic myelogenous l
eukemia-like disease due
to hematopoietic IRF8deficiency fuels atherosclerosis in mice
Circulation Research
Döring, Y., Manthey, H., Drechsler, M.,
Lievens, D., Manca, M., Hartwig, H.,
Busch, M., Koenen, R.R., Soehnlein, O.,
Zenke, M., Daemen, M.J., Weber, C.,
Lutgens, E., Zernecke, A.
Autoantigenic protein-DNA
complexes stimulate plasmacytoid dendritic cells to
promote atherosclerosis
Nature Medicine
Dressel, K., Weiller, C., Huber, W.,
Abel, S.
“Gestörter Wortabruf im
Modell und im Gehirn.
Eine Therapiestudie mit drei
Einzelfällen”
Sprache, Stimme, Gehör, 35
(1), 19-25 [IF 0.111]
Dreymueller D., Martin C., Kogel T.,
Pruessmeyer J., Hess F.M., Horiuchi K.,
Uhlig K., Ludwig A.
Lung endothelial ADAM17
regulates the acute inlammatory response to
Lipopolysaccharide
EMBO Mol Med, accepted
[IF 8,833]
Dreymueller D., Pruessmeyer J.,
Groth E., Ludwig A.
The role of ADAM-mediated
shedding in vascular biology
Eur J Cell Biol. Dec 2. [Epub
ahead of print] [IF 3,630]
Ehedego H., Boekschoten M.V.,
Muller M., Gassler N., Liedtke C.,
Trautwein C.
Loss of P21 increases
Tumorgenesis and
susceptibility to lps-iduced
liver injury in nemo
(¨hepa) animals
Hepatology 54:716A-716A
Ferreira M.V., Labude N., Piroth D.,
Jahnen-Dechent W., Knüchel R.,
Hieronymus T., Zenke M., Neuss S.
Compatibility of different
polymers for cord bloodderived hematopoietic
progenitor cells
J Mater Sci Mater Med.
doi:10.1007/s10856-0114483-4 [IF: 2.325]
6.
232
Publications 2011
Authors
Titel
Medium
Fischer C., Trajanoski S., Papić L.,
Windpassinger C., Bernert G., Freilinger
M., Schabhüttl M., Arslan-Kirchner M.,
Javaher-Haghighi P., Plecko B.,
Senderek J., Rauscher C., Löscher W.N.,
Pieber T.R., Janecke A.R.,
Auer-Grumbach M.
SNP array-based whole
genome homozygosity
mapping as the first step
to a molecular diagnosis in
patients with CharcotMarie-Tooth disease
J Neurol DOI: 10.1007/
s00415-011-6213-8
[IF 3,85]
Flick F., Lüscher B.
Regulation of sirtuin function
by posttranslational modifications
Front Pharmacol. 3:29
Gan L., Schwengberg S., Denecke B.
Micro RNA profiling during
Plos One, 6 (10) e25809
cardiomyocyte-specific
[IF 4.411]
differentiation of murine
embryonic stem cells based
on two different miRNA array
platforms
Giebeler A., Brandenburg L.,
Kaldenbach M., Erschfeld S.,
Birchmeier C., Wasmuth H.,
Trautwein C., Streetz K.L.
Lack of hepatic c-Met
and gp130 expression is
associated with an impaired
anti-bacterial response and
higher lethality after bile
duct ligation
Under revision,
Laboratory investigation
Greimel E., Schulte-Rüther M.,
Kamp-Becker I., Remschmidt H.,
Herpertz-Dahlmann B., Konrad K.
Self-report and parental
report of empathy in
adolescents with autism
Z Kinder Jugendpsychiater
Psychother 39:113-21
[IF: 0,717]
Grieb G., Piatkowski A., Simons D.,
Hörmann N., Dewor M., Steffens G.,
Bernhagen J., Pallua N.
Surgery 151:268-277
Macrophage migration
inhibitory factor is a potential [IF 3,603].
inducer of endothelial
progenitor cell mobilization
after flap operation
Grieb G., Simons D., Steinberger H.,
Vollmar A., Bernhagen J., Pallua N.
Improved in vitro cultivation
of endothelial progenitor
cells as basis for dermal
substitutes with enhanced
angiogenic capabilities
Langenbecks Arch Surg
396:1255-1262 [IF 1,951]
Guelly C., Zhu P.P., Leonardis L.,
Papic L., Zidar J., Schabhüttl M.,
Strohmaier H., Weis J., Strom T.M.,
Baets J., Willems J., De Jonghe P.,
Reilly M.M., Fröhlich E., Hatz M.,
Trajanoski S., Pieber T.R., Janecke A.R.,
Blackstone C., Auer-Grumbach M.
Targeted high-throughput
sequencing identifies
mutations in atlastin-1 as a
cause of hereditary sensory
neuropathy type I
Am J Hum Genet. 88(1):
99-105, 2011 [IF 11,7]
Heymann F., Hammerich L.,
Storch D., Bartneck M., Huss S.,
Rüsseler V., Gassler N., Lira S.A.,
Luedde T., Trautwein C., Tacke F.
Hepatic macrophage
migration and differentiation
critical for liver fibrosis is
mediated by the chemokine
receptor CCR8
Hepatology
IZKF Aachen Progress Report 2011
Publications 2011
6.
IZKF Aachen Progress Report 2011
233
Authors
Titel
Medium
Hristov M., Weber C.
Differential role of monocyte
subsets in atherosclerosis
Thromb Haemost 106:757-62
[IF 4.7]
Hoss M., Apel C., Dhanasingh A.,
Suschek C. V., Hemmrich K., Salber J.,
Zenke M., Neuss, S.
Integrin alpha4 impacts
J. Tissue Eng. Reg. Med.,
on differential adhesion of
in press
preadipocytes and stem cells [IF 3.86]
on synthetic polymers
Johann S., Dahm M., Kipp M., Zahn U.,
Beyer C.
Regulation of ChAT expres- J Neuroendocrinol 23:839sion by oestrogen in NSC-34 848 [IF 4.7]
cells and in the spinal cord
Johnen S., Kazanskaya O.,
Armogan N., Stickelmann C.,
Stöcker M., Walter P., Thumann G.
Endogenic regulation of
proliferation and zinc
transporters by pigment
epithelial cells nonvirally
transfected with PEDF
Invest Ophthalmol Vis Sci.
2011 Jul 23; 52(8):5400-7
[IF 3.466]
Johnen S., Wickert L., Meier M.,
Salz A.K., Walter P., Thumann G.
Presence of xenogenic
mouse RNA in RPE and IPE
cells cultured on mitotically
inhibited 3T3 fibroblasts
Invest Ophthalmol Vis Sci.
2011; 52:2871-24
[IF 3.466]
Jungblut M., Huber W., Pustelniak M.,
Schnitker R.
The impact of rhythm
complexity on brain activation during simple singing an
event-related fMRI study
Restor.Neurol.Neurosci.,
accepted ,DOI 10.3233/
RNN-2011-0619
[IF 3.71]
Kaldenbach M., Giebeler A.,
Tschaharganeh D.F., Erschfeld S.,
Wasmuth H.E., Dolle L., Floege J.,
Trautwein C., Streetz K.L.
Hepatocyte growth factor/c- Gut. 2012 Jan 27
Met signalling is important for
the selection of transplanted
hepatocytes
Kant S., Krull P., Eisner S., Leube R.E.,
Krusche C.A.
Histological and ultrastructural abnormalities in murine
desmoglein 2-mutant hearts
Kanzler I., Liehn E.A., Koenen R.R.,
Weber C.
Anti-Inflammatory therapeutic Curr Pharm Biotechnol.
approaches to reduce acute Apr 6. [Epub ahead of print]
atherosclerotic complications [IF 3.455]
Karus M., Denecke B.,
ffrench-Constant C., Wiese S.,
Faissner S.
The extracellular matrix
molecule tenascin C modulates expression levels and
territories of key patterning
genes during spinal cord
astrocyte specification
Khouri C., Dittrich A., Sackett S.D.,
Denecke B., Trautwein C., Schaper F.
Glucagon counteracts
Biological Chemistry,
interleukin-6-dependent gene 392, 1123-1134
expression by redundant
[IF 3.603]
action of Epac and PKA
Cell Tissue Res in press
[IF 2.8]
Development,
138 (24) 5321-5331
[IF 6.898]
Kim K.W., Vallon-Eberhard A.,
In vivo structure/function and Blood. 118:e156-67
Zigmond E., Farache J., Shezen E.,
expression analysis of the
[IF 10,558]
Shakhar G., Ludwig A., Lira S.A., Jung S. CX3C chemokine fractalkine
6.
234
Publications 2011
Authors
Titel
Medium
Kipp M., Gingele S., Pott F., Clarner T.,
van der Valk F., Denecke B., Gan, L.,
Siffrin V., Zipp F., Dreher W.,
Baumgartner W., Pfeifenbring S.,
Godbout R., Amor S., Beyer C.
BLBP-expression in astrocytes during experimental
demyelination and in human
multiple sclerosis lesions
Brain, Behavior, and
Immunity, 25 (8) 1554-1568
[IF 3.956]
Kircher T.*, Pohl A.*, Krach S.,
Thimm M., Schulte-Rüther M.,
Anders S., Mathiak K.
Affect-Specific Activation of
Shared Networks for Perception and Execution
of Facial Expressions
Social Cognitive and
Affective Neuroscience
[IF 4.482]
Klann J., Huber W.
Situationsmodell und
narrative Shifts:
Voruntersuchungen zur
Diagnostik von sprachlichen
und kognitiven Verstehensproblemen bei hirngeschädigten Patienten
Sprache Stimme Gehör
35:26-31
[IP: 0,172]
Klann J.
Psycholinguistik und
Neurolinguistik der
Gebärdensprachen
Handbuch der
Gebärdensprache
Klann J.
Verstehen sie Sprache…
in Gebärden auch mit links?
Anthropologie, Rezeption,
Transkulturation, Episteme,
Sprache - Jahrbuch der
a.r.t.e.s.
Klann J.
Berlin:
“Zur Rolle der Ikonizität in
Mouton de Gruyter
Gebärdensprachen untersucht am Beispiel der
(monography)
deutschen Gebärdensprache”
Klasen M., Weber R., Kircher T. T.,
Mathiak K. A., Mathiak, K.
Epub ahead of print
Neural contributions to
flow experience during video [IF 4.482]
game playing. Social
Cognitive and Affective
Neuroscience
Ko K., Reinhardt P., Tapia N.,
Schneider R.K., Araúzo-Bravo M.J.,
Han D.W., Greber B., Kim J., Kliesch S.,
Zenke M., Schöler H.R.
Evaluating the potential of
putative pluripotent cells
derived from human testis
Stem Cells 29, 1304-1309
[IF 7.871]
Koten J.W. Jr., Lonnemann J.,
Willmes K., Knops A.
Micro and macro pattern
analyses of FMRI data
support both early and late
interaction of numerical and
spatial information
Frontiers in Human
Neuroscience. 2011;5:115
[IF 1.94]
Kramp B.K., Sarabi A., Koenen R.R.,
Weber C.
Heterophilic chemokine
receptor interactions in
chemokine signaling and
biology
Exp Cell Res. 317:655-663
[IF 3.609]
IZKF Aachen Progress Report 2011
Publications 2011
6.
IZKF Aachen Progress Report 2011
235
Authors
Titel
Medium
Kraemer S., Weber C., Bernhagen J.
MIF and the chemokine axis
The MIF Handbook, chapter
I-2; World Scientific Press;
in press
Kray, Lenz, Spöler, Kurz
Increased tissue contrast by Proc. SPIE 8092, 809209
high-resolution simultaneous
dual-band optical coherence
tomography in three
dimensions
Kray, Lenz, Spöler, Kray, Schrage, Kurz
Pathogenesis oft he dry eye
syndrome observed by
optical coherence tomography in vitro
Proc. SPIE 8091, 809126
Krusche C.A., Holthöfer B., Hofe V.,
van de Sandt A.M., Eshkind L.,
Bockamp E., Merx M.W., Kant S.,
Windoffer R., Leube R.E.
Desmoglein 2 mutant mice
develop cardiac fibrosis
and dilation
Basic Res Cardiol [IF 6.12]
Lettow I., Schmitz P., Berres M.L.,
Müller T., Berg T., Neumann U.P.,
Trautwein C., Wasmuth H.E.
A Duffy antigen receptor for Hum Immunol 72: 273-277
[IF 2.55]
chemokines (DARC) polymorphism which determines
pro-fibrotic chemokine serum
concentrations is not directly
associated with progression
of hepatitis C infection
Lichte P., Pape H.C., Pufe T.,
Kobbe P., Fischer H.
Scaffolds for bone healing:
Concepts, Materials and
Evidence
Liehn E.A., Piccinini A.M., Koenen R.R.,
Soehnlein O., Adage T., Fatu R.,
Curaj A., Popescu A., Zernecke A.,
Kungl A.J., Weber C.
J Am Coll Cardiol 56:1847-57
A new MCP-1/CCL2
competitor limiting neointima [IF 11.460]
formation and myocardial
ischemia-reperfusion injury
in mice
Liehn E.A., Tuchscheerer N.,
Kanzler I., Drechsler M.,
Fraehmos L., Schuh A., Koenen R.,
Zander S., Soenhlein O., Hristov M.,
Grigorescu G., Urs A.O., Leabu M.,
Bucur I., Merx M.W., Zernecke A.,
Ehling J., Gremse F., Lammers T.,
Kiessling F., Bernhagen J., Schober A.,
Weber C.
Double-edged role of the
CXCL12-CXCR4 axis in
experimental myocardial
infarction
J Am Coll Cardiol 2011;
58:2415-23
[IF 14.210]
Lippe R., Ohl K., Varga G., Rauen T.,
Crispin J.C., Juang Y.T., Kürten S., Tacke
F., Wolf M., Roebrock K., Vogl T., Verjans
E., Honke N., Ehrchen J.,
Foell D., Skryabin B., Wagner N.,
Tsokos GC, Roth J., Tenbrock K.
CREM_ overexpression
decreases IL-2 production,
induces a TH17 phenotype
and accelerates
autoimmunity
JMCB 2012, accepted for
publication
[IF 13.4]
Injury 42:569-573
6.
236
Publications 2011
Authors
Titel
Lizama C., Ludwig A., Moreno R.D.
Etoposide induces apoptosis Biochim Biophys Acta.
and upregulation of TACE/
1813:120-8
ADAM17 and ADAM10 in
[IF 4,733]
an in vitro male germ cell
line model
Lüdike P., Hendgen-Cotta U.B.,
Sobierajski J., Totzeck M., Reeh M.,
Dewor M., Lue H., Krisp C., Wolters D.,
Kelm M., Bernhagen J.*, Rassaf T.*
Cardioprotection through S- Circulation, in press
nitros(yl)ation of macrophage [IF 14.816].
migration inhibitory factor
Ludwig A., Sommer A., Uhlig S.
Assessment of endothelial
permeability and leukocyte
transmigration in human
endothelial cell monolayers
Lüscher B., Vervoorts J.
Regulation of gene transcrip- Gene, in Press
tion by the oncoprotein MYC [IF: 2,26]
Mathiak K., Ackermann H., Rapp A.,
Mathiak K.A., Shergill S., Riecker A.,
Kircher T.T.J.
Neuromagnetic oscillations
and hemodynamic correlates of P50 suppression in
schizophrenia
Matute-Bello G., Downey G., Moore B.B.,
Groshong S.D., Matthay M.A.,
Slutsky A.S., Kuebler W.M. on behalf
of the Acute Lung Injury in Animals
Study Group*
An Official American Thoracic Am J Respir Cell Mol Biol
44: 725-738.
Society Workshop Report:
Features and Measurements
of Experimental Acute Lung
Injury in Animals
Megens R.T., Kemmerich K., Pyta J.,
Weber C., Soehnlein O.
Intravital imaging of
phagocyte recruitment
Müller M., Stockmann M., Malan D.,
Wolheim A., Tischendorf M., Linta L.,
Katz S.-F., Lin Q., Latz S., Brunner C.,
Wobus A. M., Zenke M., Wartenberg M.,
Böckers T. M., von Wichert G.,
Fleischmann B., Liebau S., Kleger A.
Ca2+-activated K+-channels Stem Cell Rev. and Rep.,
- New tools to induce cardiac in press
commitment from pluripotent [IF 3.766]
stem cells in mice and men
Neuss S., Denecke B., Gan L., Lin Q.,
Bovi M., Apel C., Wöltje M.,
Dhanasingh A., Salber J., Knüchel R.,
Zenke M.
Transcriptome analysis of
MSC and MSC-derived
osteoblasts on Resomer®
LT706 and PCL: impact of
biomaterial substrate on
osteogenic differentiation
PLoS One. 6:e23195
[IF: 4.411]
Opländer C., Suschek C.V.
Dermal Nitrite Application:
An Update
Journal of Investigative
Dermatology: 131:
1763–1765 (2011)
[IF 6.270]
IZKF Aachen Progress Report 2011
Medium
Methods Mol Biol.
763:319-32
Neuroimaging, 194, 95-104.
[IF 3.435]
Thromb Haemost.
105(5):802-10
[Impact 4.701]
Publications 2011
6.
IZKF Aachen Progress Report 2011
237
Authors
Titel
Medium
Opländer C., Hidding H., Werners F.B.,
Born M., Pallua N., Suschek C.V.
Effects of blue light irradiation J Photochem Photobiol B
on human dermal fibroblasts 103(2): 118-25. (2011)
[IF 2.116]
Opländer C., Romer A.,
Paunel-Görgülü A., Fritsch T.,
van Faassen E.E., Mürtz M., Bozkurt A.,
Grieb G., Fuchs P., Pallua N.,
Suschek C.V.
Kinetics and biological
responses of dermal
application of nitric oxide in
vivo: Therapeutical potential
in humans
Clinical Pharmacology &
Therapeutics
(accepted Dez 2011)
[IF 6.378]
Opländer C., Volkmar C.M.,
Paunel-Görgülü A., Fritsch T.,
van Faassen E.E., Mürtz M.,
Grieb G., Bozkurt A., Hemmrich K.,
Windolf J., Suschek C.V.
Dermal application of nitric
oxide significantly reduces
blood pressure in humans
Nitric Oxide – Biol. Ch.
(accepted Jan 2012)
[IF 3.384]
Regenbogen C., Schneider D.,
Finkelmeyer A., Kohn N., Kellermann T.,
Habel U.
The differential contribution Cognition & Emotion, 13,
of facial expression, prosody, 1-20
and speech content to
empathy
Roemgens A., Misiak M., Beyer C.,
Arnold S.
Inducers of chemical hypoxia Neurotox Res 20:1-14
[IF 3.0]
act in a gender- and brain
region-specific manner on
primary astrocyte viability
and cytochrome c oxidase
Rudnik-Schöneborn S., Arning L.,
Epplen J.T., Zerres K.
SETX gene mutation in a
family diagnosed autosomal
dominant proximal spinal
muscular atrophy
Neuromuscul Disord DOI:
10.1016/j.nmd.2011.09.006
[IF 2,62]
Sachs O., Weis S., Zellagui N., Sass K.,
Huber W., Zvyagintsev M., Mathiak K.,
Kircher T.
How different types of
conceptual relations modulate brain activation during
semantic priming
Journal of Cognitive
Neuroscience, 70(4),
1263-1273
[IF: 5.357]
Sahin H., Berres M.L., Wasmuth H.E.
Therapeutic potential of
chemokine receptor antagonists for liver disease
Expert Rev Clin Pharmacol.
2011 Jul;4(4):503-13
Sarabi A., Kramp B.K., Drechsler M.,
Hackeng T.M., Soehnlein O., Weber C.,
Koenen R.R., von Hundelshausen P.
CXCL4L1 inhibits angiogenesis and induces
undirected endothelial cell
migration without affecting
endothelial cell proliferation
and monocyte recruitment
J Thromb Haemost.
9:209-219
[IF 5.439]
Sass K., Habel U., Huber W., Sachs O.,
Gauggel S., Kircher T.
The influence of emotional
associations on the neural
correlates of semantic
priming
Human Brain Mapping, doi:
10.1002/hbm.21241
[IF: 5.107]
6.
Publications 2011
Authors
Titel
Medium
Schellenberg A., Lin Q., Schüler H.,
Koch C.M., Joussen S., Denecke B.,
Walenda G., Pallua N., Suschek C.V.,
Zenke M., Wagner W.
Replicative senescence of
AGING (Albany NY),
mesenchymal stem cells
3 (9) 873-888
causes DNA-methylation
[IF 2.964]
changes which correlate with
repressive histone marks
Schock L., Schwenzer M., Sturm W.,
Mathiak K.
Alertness and visuospatial
attention in clinical
depression
Schuh A., Sasse A., Konschalla S.,
Kroh A., Merx M.W., Weber C.,
Liehn E.A.
Repetitive transplantation of J Cell Mol Med. 2011; Epub
different cell types sequenahead of print
tially improves heart function [IF 4,603]
after infarction
Schuh A., Kroh A., Konschalla S.,
Liehn E.A., Sobota R., Biessen E.,
Bot I., Sasse A., Weber C.
Myocardial regeneration by
transplantation of modified
endothelial progenitor cells
expressing SDF-1 in a rat
model
Schwarz S., Wong J. E., Bornemann J.,
Hodenius M., Himmelreich U.,
Richtering W., Hoehn M., Zenke M.,
Hieronymus, T.
Polyelectrolyte coating of iron Nanomedicine, in press,
oxide nanoparticles for MRI- http://dx.doi.org/10.1016/
based cell tracking
j.nano.2011.08.010
[IF 4.882]
Sicking E.M., Fuss A., Uhlig S.,
Jirak P., Dijkman H., Wetzels J.,
Engel D.R., Urzynicok T., Kriz W.,
Kurts C., Ostendorf T., Floege J.,
Smeets B., Moeller M.J.
Subtotal Ablation of Parietal
Epithelial Cells results in
Cellular Activation and
Crescent Formation
J Am Soc Nephrol; in press
[IF 8.2]
Soehnlein O., Wantha S.,
Simsekyilmaz S., Döring Y.,
Megens R.T., Mause S.F.,
Drechsler M., Smeets R., Weinandy S.,
Schreiber F., Gries T., Jockenhoevel S.,
Möller M., Vijayan S.,
van Zandvoort M.A., Agerberth B.,
Pham C.T., Gallo R.L., Hackeng T.M.,
Liehn E.A., Zernecke A., Klee D.,
Weber C.
Neutrophil-derived
cathelicidin protects from
neointimal hyperplasia
Sci Transl Med. 2011 Oct 5;
3(103):103ra98
[IF 3.292]
BMC Psychiatry 11:78
[IF 2,89]
J Cel Moll Med 2011,
in press
[IF 4,603]
Straube B., Green A., Sass K., Kirner A., Neural integration of speech Human Brain Mapping
Kircher T.
and gesture in schizophrenia: [IF: 5.107]
Evidence for dysfunctional
processing of metaphoric
gestures
Sturm W., Schnitker R., Grande M.,
Huber W., Willmes K.
238
IZKF Aachen Progress Report 2011
Common networks for selective auditory attention for
sounds and words? An fMRI
study with implications for
attention rehabilitation
Restorative Neurology and
Neuroscience, 29 (2011),
S. 73–83
[IF 3.71]
Publications 2011
6.
IZKF Aachen Progress Report 2011
239
Authors
Titel
Medium
Simons D., Grieb G., Hristov M.,
Pallua N., Weber C., Bernhagen J.,
Steffens G.
Hypoxia-induced endothelial J Cell Mol Med 15:668-678
secretion of macrophage
[IF 5,228]
migration inhibitory factor and
role in endothelial progenitor
cell recruitment
Thumann G.
Nonviral gene therapy for
age-related macular
degeneration
Expert Review of
Ophthalmology, 2011;
6: 81-93
Thumann G., Armogan N.,
Schwanz T., Gaebler A., Vehr A.K.,
Walter P., Mazinani B.
Fulminant postoperative
endophthalmitis due to
streptococcus pneumoniae
Klin Monbl Augenheilkd.
2011; 228:1108-9
[IF 0,407]
Vasina E.M., Cauwenberghs S.,
Microparticles from apoptotic Cell Death Dis. 2:e210
Feijge M.A., Heemskerk J.W., Weber C., platelets promote resident
[IF due for 2012]
Koenen R.R.
macrophage differentiation
Villa L., Boor P., Koniecnzy A.,
Kunter U., van Roeyen C.R.,
Denecke B., Gan L., Kupper M.B.,
Hoffmann K., Eitner F., Ostendorf T.,
Floege J.
Effects and mechanisms of
angiotensin II receptor
blockade with telmisartan in
a normotensive model of
mesangiooroliferative
nephritis
Nephrology Dialysis
Transplantation, 26 (10)
3131-3143
[IF 3.564]
Wasmuth H.E., Trautwein C.
Prediction of fibrosis
progression in hepatitis C
infection: Are genetics ready
for clinical use?
J Hepatol 55: 3-4 (editorial)
Weber C., Meiler S., Döring Y.,
Koch M., Drechsler M., Megens R.T.,
Rowinska Z., Bidzhekov K., Fecher C.,
Ribechini E., van Zandvoort M.A.,
Binder C.J., Jelinek I., Hristov M.,
Boon L., Jung S., Korn T., Lutz M.B.,
Förster I., Zenke M., Hieronymus T.,
Junt T., Zernecke A.
CCL17-expressing dendritic J Clin Invest. 121(7):
cells drive atherosclerosis by 2898–2910
restraining regulatory T cell [Impact 14.152]
homeostasis in mice
Weinandy S., Rongen L., Schreiber F.,
Cornelissen C., Flanagan T.C.,
Mahnken A.H., Gries T.,
Schmitz-Rode T., Jockenhoevel S.
The BioStent – Novel
Concept for a Viable Stent
Structure
Tissue Eng. Part A
(accepted with revision,
revision submitted)
[IF 4.636]
Weis J.*, Katona I.*, Müller-Newen G.,
Sommer C., Necula G., Hendrich C.,
Ludolph A.C.
Small fiber neuropathy in
ALS patients
Neurology. 76(23): 2024-9,
2011 *Equal contribution
[IF 8,0]
Weiss E.M., Schmidt A., Vobis D.,
Garbi N., Lahl K., Mayer C.T.,
Sparwasser T., Ludwig A., Suri-Payer E.,
Oberle N., Krammer P.H.
Foxp3-mediated suppression J Immunol. 187:1684-91
of CD95L expression confers [IF 5,757]
resistance to activationinduced cell death in
regulatory T cells
6.
240
Publications 2011
Authors
Titel
Medium
Würflinger T., Gamper I., Aach T.,
Sechi, A.S.
Automated segmentation
and tracking for large scale
analysis of focal adhesion
dynamics
J. Microsc. 241: 37-53
[IF: 1.872]
Zhou Z., Subramanian P., Sevilmis G.,
Globke B., Soehnlein O., Karshovska E.,
Megens R., Heyll K., Chun J.,
Saulnier-Blache J.S., Reinholz M.,
van Zandvoort M., Weber C., Schober A.
Lipoprotein-Derived
Lysophosphatidic Acid
Promotes Atherosclerosis
by Releasing CXCL1 from
the Endothelium
Cell Metab. 13(5):592-600.
[Impact 18.207]
Zimmermann H.W., Seidler S.,
Gassler N., Nattermann J., Luedde T.,
Trautwein C., Tacke F.
Interleukin-8 Is Activated in
PLoS One. 6(6): e21381
Patients with Chronic Liver
Diseases and Associated
with Hepatic Macrophage
Accumulation in Human Liver
Fibrosis
Zimmermann H.W., Tacke F.
Modification of chemokine
pathways and immune
cell infiltration as a novel
therapeutic approach in liver
inflammation and fibrosis
IZKF Aachen Progress Report 2011
Inflamm Allergy Drug Targets.
10(6):509-36.
6.
IZKF Aachen Progress Report 2011
241
Progress Report IZKF Aachen 2011

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