Cardiac-specific Therapy Targeting Hypertrophy And Apoptotis
Funder
National Health and Medical Research Council
Funding Amount
$542,683.00
Summary
We have discovered that certain pathological responses in the heart are mediated by an unusual type of signalling protein. The aim of the proposed studies is to determine whether this unusual signalling mechanism can provide a good target for development of new therapeutic approaches to prevent or treat heart failure.
Function Of The S100A1 Ca2+-binding Protein Under Physiological And Pathological Conditions
Funder
National Health and Medical Research Council
Funding Amount
$452,545.00
Summary
The S100A1 protein is one of the most abundant proteins in human heart muscle cells. It binds calcium ions and may play a role in the regulation of heart function. S100A1 levels are reduced in human heart failure, but it is unclear whether this reduction contributes to worsening of the disease. To study this, we have generated a genetically modified mouse strain that cannot make the S100A1 protein. We will use these mice to study how important the protein is for heart function under normal condi ....The S100A1 protein is one of the most abundant proteins in human heart muscle cells. It binds calcium ions and may play a role in the regulation of heart function. S100A1 levels are reduced in human heart failure, but it is unclear whether this reduction contributes to worsening of the disease. To study this, we have generated a genetically modified mouse strain that cannot make the S100A1 protein. We will use these mice to study how important the protein is for heart function under normal conditions, and how it contributes to the development of heart failure. Preliminary data indicate that adult mice with reduced S100A1 protein levels develop a form of heart disease that significantly reduces the efficiency of the pump function of the heart.Read moreRead less
Cellular Localisation Of Mineralocorticoid Receptor-mediated Vascular Inflammation And Cardiac Fibrosis.
Funder
National Health and Medical Research Council
Funding Amount
$476,264.00
Summary
Cardiovascular disease is a major health and economic burden throughout the world, especially in developed countries and is the leading cause of death and disability in Australia, claiming the lives of over 50,000 Australians each year. Heart failure accounts for many of these deaths and the incidence continues to increase. Two recent large scale clinical trials have shown a 30-35% improvement in patient outcome when a blocker for the mineralocorticoid receptor (MR) is included in current best p ....Cardiovascular disease is a major health and economic burden throughout the world, especially in developed countries and is the leading cause of death and disability in Australia, claiming the lives of over 50,000 Australians each year. Heart failure accounts for many of these deaths and the incidence continues to increase. Two recent large scale clinical trials have shown a 30-35% improvement in patient outcome when a blocker for the mineralocorticoid receptor (MR) is included in current best practice therapy for either heart failure or after a heart attack. The mechanisms underlying these benefits remain to be identified. We have shown that the hormone aldosterone and its receptor, the MR, not only play an important role in the development of high blood pressure but also the progression of cardiac disease. Our most recent studies have shown that blocking the MR not only prevents cardiac fibrosis and vascular damage, but also reverses this process. To understand the mechanisms that translate MR signalling into blood vessel damage and cardiac fibrosis we wish to use mice who have the MR gene inactivated in specific cells only. In this way we can identify those cells critical to the disease process and focus our investigations to these cell types. Understanding the cell specific regulatory mechanisms for the MR may enable the development of heart-specfic blockers of the MR that have minimal, if any side effects.Read moreRead less
Studying The Novel Role For G Protein-coupled Receptor Signalling In Leukaemia Development
Funder
National Health and Medical Research Council
Funding Amount
$373,144.00
Summary
Recent research has shown the clinical importance of abnormal stem cells (LSC) in acute myeloid leukaemia (AML). LSC are resistant to therapeutics suggesting that they could be a cause of relapse. Identifying signalling pathways that drive LSC development is essential to selectively eradicate LSC that could offer substantial therapeutic benefit. This proposal aims to identify and evaluate critical signalling pathways as a potential therapeutic target for developing effective novel LSC-targeted t ....Recent research has shown the clinical importance of abnormal stem cells (LSC) in acute myeloid leukaemia (AML). LSC are resistant to therapeutics suggesting that they could be a cause of relapse. Identifying signalling pathways that drive LSC development is essential to selectively eradicate LSC that could offer substantial therapeutic benefit. This proposal aims to identify and evaluate critical signalling pathways as a potential therapeutic target for developing effective novel LSC-targeted therapy in AML.Read moreRead less
New CaMKII Therapeutic Targets In Heart Failure With Preserved Ejection Fraction
Funder
National Health and Medical Research Council
Funding Amount
$740,335.00
Summary
Deaths associated with impaired heart muscle relaxation and unstable cardiac cycle rhythm are increasing. The mechanisms by which these pathologies occur are not understood and clinical therapies are lacking. We have novel evidence to suggest that a key signalling protein, CaMKII, is critically involved in the development of these forms of heart pathology. This goal of this project is to identify how CaMKII is implicated in heart failure and dysrhythmia as a basis for designing new therapies.
Formyl Peptide Receptor Biased Agonists As Novel Cardioprotective Agents Against Myocardial Infarction.
Funder
National Health and Medical Research Council
Funding Amount
$318,768.00
Summary
Heart attack and its resulting heart failure are the leading causes of death in Australia. Examining a promising new target (formyl peptide receptors), I will use my knowledge of drug action at the single cell level to identify new drugs that act via a unique biased mechanism. These will be tested in pre-clinical animal models of heart attack to uncover critical new potential therapies that will protect the heart post heart attack and prevent the development heart failure.
Regulation Of Calcium Release Channels (RyR2) In Healthy And Failing Hearts
Funder
National Health and Medical Research Council
Funding Amount
$337,632.00
Summary
In striated muscle, the sarcoplasmic reticulum (SR) is the calcium store from which calcium release through ryanodine receptors (RyR2) is the key determinate of muscle force. We will develop an understanding of the complex functional changes in RyR2 that underlie adaptation of the heart to physiological stress (exercise) and functional changes associated with mal-adaptation in heart failure.
Identifying And Developing Novel Therapeutic Approaches For Heart Disease
Funder
National Health and Medical Research Council
Funding Amount
$638,517.00
Summary
Increasing rates of obesity, diabetes, and an ageing population increase the risk of heart disease & complications including heart failure (HF), atrial fibrillation (AF), and diabetic heart disease. There is a clinical need for i) improved therapies for patients with HF, AF, and diabetic heart, and ii) biomarkers which more effectively recognise people at risk of heart disease, to prevent clinical events. My research program is designed to develop novel therapies and identify new biomarkers.
SHANK3 As A Target To Reduce Hypertrophy And Heart Failure
Funder
National Health and Medical Research Council
Funding Amount
$548,908.00
Summary
We have identified a large protein in heart that functions to facilitate the heart's response to disease. The proposed studies will define how this protein mediates responses and whether we can successfully interfere with the process to limit disease progression.
Inositol Polyphosphate 1-phosphatase, A Novel Anti-hypertrophic Factor
Funder
National Health and Medical Research Council
Funding Amount
$399,750.00
Summary
Growth of the heart muscle cells occurs after heart attack and in people with high blood pressure or who suffer from diseases such as diabetes. Such growth leads eventually to the development of heart failure, a major cause of death and disability in western societies. We have identified a novel inhibitor of this growth, an enzyme that destroys a signalling intermediate called inositol(1,4)bisphosphate (or IP2). We now need to define how reduction in IP2 reduces growth and whether it provides a ....Growth of the heart muscle cells occurs after heart attack and in people with high blood pressure or who suffer from diseases such as diabetes. Such growth leads eventually to the development of heart failure, a major cause of death and disability in western societies. We have identified a novel inhibitor of this growth, an enzyme that destroys a signalling intermediate called inositol(1,4)bisphosphate (or IP2). We now need to define how reduction in IP2 reduces growth and whether it provides a useful target for therapy.Read moreRead less