Molecular Mechanisms Of Inherited Cardiomyopathies
Funder
National Health and Medical Research Council
Funding Amount
$611,574.00
Summary
Heart failure due to disorders of the heart’s contraction and rhythm is a major health burden for our community. Two of the most common causes of heart failure are dilated cardiomyopathy (DCM) and atrial fibrillation (AF). The broad objective of DF’s research is identification of genetic variants that cause familial forms of DCM and AF, and elucidation of the pathophysiological effects of these variants. A better understanding of disease mechanisms will facilitate new approaches to diagnosis, tr ....Heart failure due to disorders of the heart’s contraction and rhythm is a major health burden for our community. Two of the most common causes of heart failure are dilated cardiomyopathy (DCM) and atrial fibrillation (AF). The broad objective of DF’s research is identification of genetic variants that cause familial forms of DCM and AF, and elucidation of the pathophysiological effects of these variants. A better understanding of disease mechanisms will facilitate new approaches to diagnosis, treatment and prevention.Read moreRead less
The Structural Basis For The Control Of Cardiac And Skeletal Muscle By The Troponin Complex
Funder
National Health and Medical Research Council
Funding Amount
$369,003.00
Summary
Many key physiological processes are controlled by large, multi-protein complexes. These molecular machines ensure that signals transmitted in the body are correctly interpreted and amplified so as to control key body functions. The Troponin protein complex is one such large multi-protein complex which is the switch used to control both heart and skeletal muscle contraction in the body. The Troponin complex responds to increasing cellular calcium levels, switching the muscle on at high calcium. ....Many key physiological processes are controlled by large, multi-protein complexes. These molecular machines ensure that signals transmitted in the body are correctly interpreted and amplified so as to control key body functions. The Troponin protein complex is one such large multi-protein complex which is the switch used to control both heart and skeletal muscle contraction in the body. The Troponin complex responds to increasing cellular calcium levels, switching the muscle on at high calcium. When calcium returns to its normal basal level, the Troponin complex switches the muscle off. Naturally occurring genetic errors can lead to the malfunction of the Troponin complex. This, in turn, can lead to severe and possibly fatal diseases of the heart and muscle systems. To gain an understanding of these molecular diseases, it is important to understand the structure, dynamics and function of the Troponin complex. This project will use a newly-developed magnetic resonance method to monitor changes in the Troponin structure as a function of calcium level. Each component of the Troponin complex will be labeled with magnetic tags, allowing the determination of both structure and dynamics of Troponin, both in solution and in active muscle fibres. The study will result in a molecular understanding of how the Troponin switch works. This will give great insight in how mutations result in cardiac and muscular diseases.Read moreRead less
TRANSCRIPTIONAL AND FUNCTIONAL CONSEQUENCES OF STAT3 ACTIVATION IN THE HEART
Funder
National Health and Medical Research Council
Funding Amount
$413,694.00
Summary
Recent statistics show that the disease known commonly as heart failure accounts for about 3000 deaths each year in Australia. Worldwide, a staggering 10 million people are thought to currently suffer from heart failure, with this number continuing to rise despite decreasing numbers of people suffering from other forms of heart and blood vessel disease. What causes a healthy heart to fail remains unclear, although in some circumstances failure is known to be initiated by genetic factors, viral f ....Recent statistics show that the disease known commonly as heart failure accounts for about 3000 deaths each year in Australia. Worldwide, a staggering 10 million people are thought to currently suffer from heart failure, with this number continuing to rise despite decreasing numbers of people suffering from other forms of heart and blood vessel disease. What causes a healthy heart to fail remains unclear, although in some circumstances failure is known to be initiated by genetic factors, viral factors, alcoholism, high blood pressure, or when the heart is damaged in a heart attack. We are interested in the molecular mechanisms that underlie the progression of the normal heart to failure. In 2003 we reported on altered signalling pathways in the failing human heart, and noted the increased phosphorylation of a spliceform of the transcription factor STAT3 in patients with heart failure. In this project, we will evaluate a larger group of heart failure patients for changes in phosphorylation of their STAT3 proteins. We will also increase the expression of an activated form of the STAT3 proteins in rat heart cells, and check whether there are accompanying changes in gene expression profiles that indicate a potential role in heart failure, or whether these cells are now predisposed to die. This will be extended with the use of transgenic animals (mice) engineered to overexpress activated STAT3 proteins. Again, we will focus on gene expression profiles. We will also evaluate whether the hearts of these animals are more likely to fail, either as the animals age, or when external stresses are experienced. With this information, we will be able to state whether STAT3 is a contributor to heart failure, and therefore whether it is an attractive target for future therapies aimed at reducing the morbidity and mortality of heart failure worldwide.Read moreRead less
Development Of A Bioinformatic Tool For The Rapid Identification Of Candidate Disease Genes
Funder
National Health and Medical Research Council
Funding Amount
$436,367.00
Summary
Candidate disease gene prediction systems assist geneticists by using biological data to suggest genes likely to be causative of diseases in regions of the genome delineated by genetic studies. This area has been enabled by completion of the Human Genome Project and increased availability of high-throughput experimental data and sophisticated bioinformatic tools. Identification of disease genes will contribute to an understanding of disease, as well as its prevention, diagnosis, and treatment.
C-Jun N-terminal Kinase Regulation Of Microtubule Destabilizer, Stathmin - A Novel Cytoprotective Pathway
Funder
National Health and Medical Research Council
Funding Amount
$550,230.00
Summary
The loss of heart muscle cells during heart attack and heart failure worsens the severity of heart disease. We will study how to protect heart muscle cells by identifying the molecules involved in controlling survival responses. We will use this knowledge to prevent heart muscle cells from dying when exposed to a range of normally harmful conditions. Our study has the potential to prevent heart muscle cell loss, improve heart function and prevent muscle damage in heart disease.
Research Fellowship: Protection Of Myocardial Function In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$631,010.00
Summary
Heart failure (HF) is a major cause of death in Australia. A/Prof Rebecca Ritchie heads Heart Failure Pharmacology at Baker IDI. Her research focuses on new drug strategies to maintain heart function in response to diabetes & heart attack, common precursors of HF. Many of the treatments discovered from this work are naturally-occurring antioxidants; enhancing their activity will ultimately reduce progression to HF & death in the >3 million Australians affected by these disorders.
Dissecting The Pathogenesis Of The Severe Neurodegenerative Disease, Friedreich’s Ataxia: Development Of Novel Therapeutics
Funder
National Health and Medical Research Council
Funding Amount
$316,449.00
Summary
Friedreich’s ataxia is a devastating neuro- and cardio-degenerative disorder which does not have an effective cure. The studies proposed in this Fellowship are crucial for understanding the progression of this disorder and the development of excitingly new therapeutics.