A / PROF JULIE MCMULLEN CARDIAC HYPERTROPHY CELL SIGNALLING & METABOLISM

CELL SIGNALLING & METABOLISM
KEY FACTS
A / PROF JULIE MCMULLEN
Team
Researchers: 5
Students: 4
Postdoc fellows: 3
CARDIAC HYPERTROPHY
Translation
Patents: 1
Links
USA, Japan
Keywords
Cardiac hypertrophy
Heart failure
Atrial fibrillation
Signalling
Bio-resources
Genetic mouse models
Adeno-associated virus
The goal of our laboratory is to develop better treatment
strategies for patients with heart failure and atrial fibrillation by
studying molecular mechanisms in genetic mouse models and
cell culture.
Research Brief
Our research is focused on identifying genes/proteins that mimic the protective
effects of exercise. Growth of the heart (also termed cardiac hypertrophy) can be
induced by physiological stimuli (e.g. chronic exercise training) or pathological
stimuli (e.g. high blood pressure). Physiological hypertrophy (“good” heart growth)
is characterised by normal or enhanced heart function; whereas pathological
hypertrophy (“bad” heart growth) is associated with cardiac dysfunction, and
increased morbidity and mortality. Our laboratory are examining the possibility of
activating “good” genes and signalling pathways that may normally be activated
during the induction of physiological hypertrophy e.g. in the “athlete’s heart”. We
previously reported that the insulin-like growth factor 1 (IGF-1)-phosphoinositide 3kinase (PI3K) pathway plays a critical role for the induction of exercise induced
heart growth. Thus, activation of PI3K, or targeting novel regulators of this
pathway (e.g. genes, proteins and microRNAs), represents a new strategy to treat
heart failure.
Methodologies
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Cardiac function studies (echocardiography, electrocardiography) in
genetically modified mouse models
In vivo delivery of AAV
In vivo delivery of agents that inhibit microRNA
qRT-PCR, Northerns, Westerns, immunoprecipitation, kinase assays, cell
culture
Selected Publications
CONTACT
Julie McMullen
+61 (3) 8532 1194
julie.mcmullen@
bakeridi.edu.au
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Bernardo BC, Gao XM, Winbanks CE, Boey EJ, Tham YK, Kiriazis H, Gregorevic P, Obad S,
Kauppinen S, Du XJ, Lin RC, McMullen JR*. Therapeutic inhibition of the miR-34 family attenuates
pathological cardiac remodeling and improves heart function. Proc Natl Acad Sci USA. 109:1761520, 2012.
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Weeks KL, Gao X, Du XJ, Boey EJ, Matsumoto A, Bernardo BC, Kiriazis H, Cemerlang N, Tan JW,
Tham YK, Franke TF, Qian H, Bogoyevitch MA, Woodcock EA, Febbraio MA, Gregorevic P,
McMullen JR. PI3K(p110α) Is a Master Regulator of Exercise-Induced Cardioprotection and PI3K
Gene Therapy Rescues Cardiac Dysfunction. Circ Heart Fail. 5:523-534, 2012.
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Lin RC, Weeks KL, Gao XM, Williams RB, Bernardo BC, Kiriazis H, Matthews VB, Woodcock EA,
Bouwman RD, Mollica JP, Speirs HJ, Dawes IW, Daly RJ, Shioi T, Izumo S, Febbraio MA, Du XJ,
McMullen JR. PI3K(p110α) protects against myocardial infarction-induced heart failure:
Identification of PI3K-regulated miRNAs and mRNAs Arterioscler Thromb Vasc Biol 30: 724-32,
2010.
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Pretorius L, Du XJ, Woodcock EA, Kiriazis H, Lin RCY, Marasco S, Medcalf RL, Ming Z, Head GA,
Tan J, Cemerlang N, Sadoshima J, Shioi T, Izumo S, Dart AM, Jennings GL, McMullen JR.
Reduced PI3K(p110α) increases the susceptibility to atrial fibrillation. The American Journal of
Pathology 175:998-1009, 2009.
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McMullen JR, Amirahmadi F,Woodcock EA, Schinke-Braun M, Bouwman RD, Hewitt KA, Mollica
JP, Zhang L, Zhang Y, Shioi T, Buerger A, Izumo S, Jay PY and Jennings GL. Protective effects of
exercise and PI3K(p110α) signaling in dilated and hypertrophic cardiomyopathy. Proc Natl Acad
Sci USA 104: 612-617, 2007.
BAKER IDI HEART & DIABETES INSTITUTE
CELL SIGNALLING & METABOLISM
Identifying new therapies based on differences in physiological &
pathological heart growth
PI3K gene therapy improves function of the failing heart
Single administration of adeno-associated viral vector (rAAV6) containing PI3K improves heart function (fractional
Inhibition of PI3K-regulated microRNAs can improve heart function
AntimiR was delivered to mice with pre-existing cardiac dysfunction due to pressure overload (TAC). Heart
function (fractional shortening) improved in antimiR treated mice but not control. Heart size and atrial size were
lower in antimiR-treated mice.
BAKER IDI HEART & DIABETES INSTITUTE