Metabolism and Obesity

Dr Julie McMullen
Head, Cardiac Hypertrophy
julie.mcmullen@bakeridi.edu.au

Laboratory Research Overview

The cardiac hypertrophy lab focuses on understanding heart enlargement, cardiac hypertrophy, through comparisons between models of health and disease: examining the enlarged athletic heart (physiological hypertrophy) in comparison to heart enlargement associated with disease (pathological hypertrophy).

It is well understood that the hearts of athletes grow: the super fit have a heart size greater than the average person. This enlargement is of benefit to them in their training and works to enable them to continue their level of exercise and fitness. When they stop training that healthy heart growth stops and the heart returns to a normal size. Conversely, heart failure patients commonly experience heart growth but this change is devastating. It wreaks havoc and is usually impossible to reverse.

From this observation, the team's research has focused on understanding the changes in the athlete's heart that might benefit people with heart disease, whose heart growth might be caused by hypertension and/or heart failure. Julie's studies demonstrate there are changes in genes that occur in people with cardiac hypertrophy associated with heart failure that do not occur in the athlete's heart. She has established that even though there are comparable increases in heart size, there are clear molecular and histological changes between the two. The lab is working to identify genes causing heart enlargement that are good for the heart, as opposed to those genes causing heart enlargement with detrimental effects. In doing so she hopes to reproduce the work of the "good genes" in the failing heart. Their research is novel in its suggestion that it is possible to promote and activate "good" genes in the heart as opposed to just inhibiting "bad" genes that cause the growth of the diseased heart.

The team's research involves genetically modified mouse models of heart failure. By over expressing a gene involved in the growth of the athlete's heart in a mouse model with heart failure, the team hopes to understand whether this gene might be of use to patients with heart disease, and whether its promotion and growth can negate the effects of the "bad" growth genes.

Current therapeutics are largely treating heart failure by delaying disease progression. The goal of Julie's research is to improve function of the failing heart and protect it from complications such as atrial fibrillation.

Research Focus

• Identify critical genes in the athlete's heart that provide protection
• Identify "druggable" heart-specific targets
• Examine whether activation of key genes in the athlete's heart can improve function of the failing heart
• Examine gender differences in the heart
• To reduce/rescue the incidence of atrial fibrillation
• Target microRNAs to treat heart failure and atrial fibrillation

Research Projects

Targeting novel regulators of exercise induced heart growth to treat heart failure

Group leaders: Dr Julie McMullen and Dr Bianca Bernardo

Heart failure is a major clinical problem affecting 1-3% of Australians. The number of people diagnosed with heart failure is on the rise, due to an ageing population and increased rates of obesity and diabetes, posing a significant healthcare burden. Thus, strategies to protect the heart against insults such as high blood pressure, heart failure, and heart attack are becoming even more critical. My laboratory is focused on identifying genes/proteins that mimic the protective effects of exercise. In an effort to treat patients with heart failure, the majority of investigators have focused on blocking "bad" genes and signalling pathways in the heart, which largely delays heart failure. By contrast, my 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". My group previously reported that the insulin-like growth factor 1 (IGF-1)-phosphoinositide 3-kinase (PI3K) pathway plays a critical role for the induction of exercise induced heart growth. Thus, activation of PI3K, or novel regulators of this pathway, represents a promising new strategy to treat heart failure.

We have a number of projects that can be tailored for both Honours and PhD students. Projects utilise genetic mouse models in combination with a number of molecular biology and biochemical techniques.

Novel treatment strategies to protect the heart against atrial fibrillation

Atrial fibrillation (AF) is a cardiac disorder. It is the most common type of arrhythmia causing an irregular heat beat, weakness, fatigue and dizziness. AF is associated with increased risk of mortality, stroke and heart failure. AF and heart failure may share common triggers and treatment strategies. We have identified activation of PI3K as a novel strategy for the treatment of heart failure. This project will explore whether increasing PI3K or novel targets of PI3K in the heart of mouse models with AF (using adeno-associated viral vectors or novel compounds) will protect the heart against AF.

Examining gender differences in mouse models of heart failure

Gender differences exist in the incidence of cardiovascular disease and the response to major cardiovascular drugs. Women typically develop heart disease later than men and this has been attributed to the protective actions of female sex hormones, in particular, estrogen. However, there are exceptions that are yet to be understood. For instance, diabetic women are at greater risk of developing heart failure than men in response to a cardiac insult. This project will explore the importance of the estrogen receptor ERα-PI3K interaction in female and male hearts utilising mice with cardiac-specific ERα deletion, and will characterise the phenotype of ERα knockout mouse under basal conditions and in response to pressure overload.

Targeting PI3K regulated microRNAs and novel genes to treat heart failure

microRNAs (miRs) are a family of small RNAs that play important roles in the regulation of target genes by interacting/binding with specific sites in 3'untranslated regions of messenger transcripts to repress their translation or regulate degradation. Silencing of miRs in vivo with antagomiRs is a new and expanding area of technology that is considered a powerful approach that may represent a new therapeutic strategy for targeting cardiac disease. Using microarray analysis, we have identified a number of miRs that are differentially regulated in mice with increased or decreased PI3K activity (a critical gene in the athlete's heart). This project will examine whether inhibition of miRs (i.e. mimicking what happens in a setting of physiological hypertrophy) using an antagomiR can improve cardiac function in vitro and in vivo.

Another area that this particular project can explore is the characterisation of novel genes to treat heart failure. By microarray we have identified a cohort of genes that may be important for the physiological hypertrophic response induced by the PI3K pathway. Avenues that can be undertaken include performing bioinformatics analysis of novel genes to elucidate gene/protein structure and function, characterisation of gene expression in the heart after pathological and physiological stimuli, targeting of novel genes in a setting of heart failure to determine if cardiac function has improved.

Lab Head Profile

Julie McMullen (PhD) heads the Cardiac Hypertrophy Laboratory at the Baker IDI Heart & Diabetes Institute. Dr McMullen graduated from the School of Physiology & Pharmacology at the University of New South Wales. She then trained as a Cardiology Research Fellow at Beth Israel Deaconess Medical Centre and Harvard Medical School in Boston. During this time she gained experience generating and characterising cardiac specific transgenic mice. In early 2005, Dr McMullen established her own laboratory at Baker IDI. Her research interests include cardiac hypertrophy and failure, specifically focusing on molecular mechanisms responsible for the induction of physiological and pathological cardiac hypertrophy. Dr McMullen is currently supported by an Australian Research Council Future Fellowship and holds an Honorary NHMRC Research Fellowship. She is a member of two Editorial Boards and is a Council Member of the International Society for Heart Research, Australasian section.

Achievements/Awards

Publication Highlights

• 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, Jennings GL. Protective effects of exercise and PI3K(p110α) signaling in dilated and hypertrophic cardiomyopathy. Proc Natl Acad Sci USA 2007;104:612-617. *Senior author
• 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 phosphoinositide 3-kinase(p110α) increases the susceptibility to atrial fibrillation. The American Journal of Pathology 2009;175:998-1009. *Senior author
• 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 2010;30:724-32. *Senior author
• Bernardo BC, Weeks KL, Pretorius L, McMullen JR*. Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacology & Therapeutics 2010;128:191-227. *Senior author
• Weeks KL & McMullen JR. The Athlete's Heart vs. the Failing Heart: Can Signaling Explain the Two Distinct Outcomes? Physiology 2011 26(2):97-105.
  
  
  

Staff

Contact

Direct: +613 8532 1194
Email: julie.mcmullen@bakeridi.edu.au