Molecular Cardiology
Head – Elizabeth Woodcock
liz.woodcock@bakeridi.edu.au
Laboratory Overview
Associate Professor Elizabeth Woodcock is a Principal Research Fellow of the National Health and Medical Research Council and heads Baker IDI's Molecular Cardiology laboratory.
Liz is known primarily for studies of mechanisms where the heart responds to stimulation, and how these processes contribute to heart disease. In particular, this laboratory studies mechanisms associated with the development of hypertrophy and chamber dilatation within the heart. The laboratory is best known for defining a new cause of arrhythmogenesis, leading to sudden cardiac death. Their research currently focuses on developing methods to limit hypertrophy and chamber dilatation by targeting signalling pathways that are specific to the myocardium. By limiting atrial dilatation, they hope to improve the treatment of atrial fibrillation.
The laboratory also studies the role of short non-coding RNAs called microRNAs in atrial fibrillation in humans. Here the aims are to establish factors associated with atrial fibrillation and potentially to develop protocols to identify patients at risk of developing post-operative atrial fibrillation.
Research Focus
- Phospholipase Cbeta1b and the proteins that bind it to the cardiomyocyte cell membrane where it is activated
- The role of phospholipase Cbeta1b in causing hypertrophy and chamber dilatation in vivo
- The validation of the phospholipase Cbeta1b inhibitory min-gene in vivo
- The identification of inhibitors that prevent activation of phospholipase Cbeta1b by preventing its binding to the cell membrane
- Demonstrating that the Ca2+-releasing messenger, Ins(1,4,5)P3, contributes to atrial fibrillation in a mouse model of dilated cardiomyopathy
- miR profiles in patients with valvular heart disease and how these reflect atrial fibrillation
- miR profiles in atrial samples from patients undergoing coronary artery by-pass surgery, and whether there are predictors or subsequent post-operative atrial fibrillation
Research Projects
The role of phospholipase Cbeta1b in causing hypertrophy and chamber dilatation in vivo.
The validation of phospholipase Cbeta1b inhibitors in vivo.
Group Leader: Dr. Peter Illiadis
We have shown that PLCb1b causes hypertrophy and apoptosis (cell death) of cardiomyocytes in cell culture models. We have also developed mini-gene inhibitors that interfere with PLCb1b binding to the plasma membrane and thereby prevent pathological cell growth and cell death. We are currently underway with studies to demonstrate that PLCb1b causes hypertrophy and chamber dilatation in vivo and that the mini-gene inhibitor can reduce pathology in sheep and mouse models.
Electrocardiograph - normal & dilated cardiomyopathy
Phospholipase Cbeta1b and the proteins that bind it to the cardiomyocyte cell membrane where it is activated.
Group Leader: Dr. David Grubb
In previous studies we have shown that pathological signalling responses in cardiomyocytes depend exclusively on one splice variant of a particular phospholipase C enzyme, phospholipase Cbeta 1b (PLCb1b). This exclusive activation is because only PLCb1b binds to the plasma membrane where it is active. Such binding is mediated by the splice variant specific C-terminal region of the protein. In this current project, we have identified the high MW protein SH3 and ankyrin repeat protein 3 (Shank3) as the protein that binds the C-terminal tail of PLCb1b. We showed that Shank3 also binds to another protein called a-fodrin that links it to the plasma membrane and to the cytoskeleton. We are now examining other proteins that are part of this complex.
Demonstrating that the Ca2+-releasing messenger Ins(1,4,5)P3 contribute to atrial fibrillation in a mouse model of dilated cardiomyopathy.
Group Leader: Dr. Nicola Cooley
We currently have mice that have dilated cardiomyopathy, and develop atrial fibrillation. These mice have elevated generation of Ins(1,4,5)P3 as well as heightened expression of the receptoes for this messenger (IP3-R). These mice are being crossed with mice that have receptors for Ins(1,4,5)P3 deleted in the myocardium. We predict that deletion of IP3-R will alleviate atrial fibrillation in these mice.
miR profiles in patients with valvular heart disease and how these reflect atrial fibrillation
Group Leader: Dr. Nicola Cooley
miR profiles in atrial samples from patients undergoing coronary artery by-pass surgery, and whether there are predictors of subsequent post-operative atrial fibrillation
We have identified several miRs whose expression is altered in atrial tissue from patients with valvular heart disease. We are currently identifying miRs whose expression differs between those patients who have chronic atrial fibrillation, from those who do not.
We are also identifying miRs that show a different expression pattern in atrial tissue from patient undergoing coronary artery bypass grafting who subsequently develop atrial fibrillation, post-operatively.
The development of inhibitors that prevent activation of phospholipase Cbeta1b by preventing its binding to the cell membrane.
Group Leader: Prof Elizabeth Woodcock
These studies will involve screening for compounds that prevent interaction of the C-terminal region of PLCb1b with its interaction site on Shank3.
Lab Head Profile
My undergraduate training in Biochemistry was undertaken at the University of Queensland. This was followed by a PhD in Molecular Biology whilst I was a CSIRO student, at the Division of Animal Genetics, North Ryde, Sydney. Subsequent post-doctoral studies in protein structure analysis were pursued at the University of Sydney and subsequently I changed direction to Molecular Pharmacology/Cardiology and started work in the Department of Medicine, Monash University, Melbourne. I am currently an NHMRC Principal Research Fellow and Head of Molecular Cardiology at the Baker IDI Heart and Diabetes Institute, Melbourne. I have honorary associate professorships in Biochemistry and Molecular Biology at both Monash University and the University of Melbourne. My field of research focuses on the pathological role of the Ca2+-releasing messenger Ins(1,4,5)P3 in heart disease, particularly arrhythmia and hypertrophy. I was an invited speaker on this subject at the 2010 Gordon Research Conference on Cardiac Regulatory Mechanisms.
Achievements / Awards
- Identification of Ins(1,4,5)P3 as an initiator or arrhythmia during post-ischemic reperfusion.
- Demonstration that acute dilatation of the myocardium activates phospholipase C activity.
- Identification of PLC1b as the sole mediator of pathological responses downstream of Gq, in cardiomyocytes.
- Demonstration that PLC1b expression and activity is heightened in dilated atria from humans, sheep and mice.
- Demonstration that PLC is activated acutely by myocardial ischemia.
Publication Highlights
Filtz, TM, Grubb DR, McLead-Dryden, TJ, Luo, JT, Woodcock EA. Gq-initiated cardiomyocyte hypertrophy is mediated by phospholipase C1b. FASEB J (2009);23(10):3564-3570 [IF 7.2].
Grubb DR, Vasilevski O, Huynh H, and Woodcock EA. The extreme C-terminal region of phospholipase C1 determines subcellular localization and function; the ‘b' splice variant mediates 1-adrenergic receptor responses in cardiomyocytes. FASEB J 22: 2768-2774 (2008) [IMPACT FACTOR 7.4
Morris JB, Pham TM, Kenney B, Sheppard K, Woodcock E. UTP transactivates epidermal growth factor (EGF) receptors and promotes cardiomyocyte hypertrophy despite inhibiting transcription of the hypertrophic marker gene atrial natriuretic peptide (ANP). J Biol Chem 279: 8740-8746 (2004) [IMPACT FACTOR 7.4]
Harrison SN, Autelitano DJ, Wang BH, Milano C, Du X-J, Woodcock EA. Reduced reperfusion-induced Ins(1,4,5)P3 generation and reperfusion arrhythmias in hearts expressing constitutively active 1B-adrenergic receptors. Circ Res 83: 1232-1240 (1998).
Woodcock E.A., Suss M.B. and Anderson K.E. Inositol phosphate release and metabolism in rat left atria. Circ Res 76: 252-260 (1995).
Scientific Staff
Dr Peter Iliades
Dr David Grubb
Dr Nicola Cooley
Students
Albert Wong
