Genetic Basis Of Sudden Cardiac Death In The Young
Funder
National Health and Medical Research Council
Funding Amount
$574,500.00
Summary
Sudden cardiac death is a devastating complication of a variety of cardiovascular disorders. In the young, sudden cardiac death can be caused by both structural abnormalities of the heart, e.g. cardiomyopathies, and electrical abnormalities of the heart, such as familial long QT syndrome. In most young sudden cardiac deaths, these cardiovascular disorders are caused by underlying gene abnormalities which place individuals at a higher risk of sudden death. The aim of this project is to understand ....Sudden cardiac death is a devastating complication of a variety of cardiovascular disorders. In the young, sudden cardiac death can be caused by both structural abnormalities of the heart, e.g. cardiomyopathies, and electrical abnormalities of the heart, such as familial long QT syndrome. In most young sudden cardiac deaths, these cardiovascular disorders are caused by underlying gene abnormalities which place individuals at a higher risk of sudden death. The aim of this project is to understanding the genetic basis of sudden cardiac deaths in the young. In particular, the study will identify and characterise the specific genes which cause sudden cardiac death, and what the underlying mechanism is regarding how a single gene defect can lead to such a devastating clinical outcome. Understanding the various cardiovascular diseases that cause sudden death, clinically screening at-risk individuals, coupled with the initiation of appropriate therapeutic and preventative strategies such as implantation of cardioverter defibrillators will most likely reduce the incidence of sudden cardiac death in the young of our community. Elucidation of the underlying genetic defects which cause many of these cardiac disorders will substantially improve diagnostic accuracy, will be invaluable for genetically screening at-risk individuals and by making the diagnosis earlier in life, will create a larger therapeutic window to allow initiation of therapies to prevent complications of disease, including sudden death.Read moreRead less
Key Role Of Connective Tissue Growth Factor (CTGF) In Familial Cardiomyopathy And Heart Failure
Funder
National Health and Medical Research Council
Funding Amount
$395,051.00
Summary
Familial cardiomyopathies are an important cause of heart failure and sudden death. Understanding the precise mechanisms of how disease develops in cardiomyopathies is an important step for developing new therapeutic and prevention strategies. We plan to investigate the role of connective tissue growth factor (CTGF) , an important protein which causes scar formation in the heart, in cells, mice, and humans predisposed to developing heart disease.
Modifying Factors And Phenotype Heterogeneity In Familial Hypertrophic Cardiomyopathy
Funder
National Health and Medical Research Council
Funding Amount
$394,405.00
Summary
Familial Hypertrophic Cardiomyopathy (FHC) is an inherited disorder characterised by abnormal thickening of heart muscle, resulting in clinical symptoms in affected individuals ranging from mild symptoms, to heart failure and sudden death. FHC is the commonest cause of sudden death in individuals aged less than 35 yrs in our community, and is caused by defects in genes (DNA) important in the heart's cellular structure and function. Understanding and identifying the molecular steps involved in ho ....Familial Hypertrophic Cardiomyopathy (FHC) is an inherited disorder characterised by abnormal thickening of heart muscle, resulting in clinical symptoms in affected individuals ranging from mild symptoms, to heart failure and sudden death. FHC is the commonest cause of sudden death in individuals aged less than 35 yrs in our community, and is caused by defects in genes (DNA) important in the heart's cellular structure and function. Understanding and identifying the molecular steps involved in how this defect in our DNA can lead to the clinical features of FHC, is the focus of the research described in this project. A common occurrence in families with FHC is the identification of two affected individuals within the same family (e.g. siblings) and who therefore have the same genetic defect, with variable clinical outcomes. For example, one sibling may have no symptoms and live a normal life, while his-her sibling, may develop severe symptoms, heart failure, and-or early sudden death. The reason for such diversity in clinical features, even amongst individuals with the same genetic defect, most likely reflects secondary modifying factors, e.g. genetic and-or environmental factors which modulate the expression of the primary FHC-causing gene defect. This project will focus on identifying and studying such modifying factors. One aspect of the project will focus on the identification of a genetic modifier which has been shown to exist in a genetically-engineered mouse model of FHC. A second aspect of the proposed research will focus on potential environmental factors, including pharmacological agents which may prevent disease progression, dietary factors, e.g. caffeine intake, and lifestyle factors , e.g. exercise. Through these studies, it is hoped that key molecules and important pathogenic mechanisms will be identified, leading to the development of potentially new therapies, to both treat, and ultimately prevent or cure this inherited cardiac disorder.Read moreRead less
Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. A new clinical subgroup of HCM patients who are essentially gene carriers, referred to as "Genotype Positive Phenotype Negative" has arisen as a result of genetic testing in at-risk family relatives. Little is known about the natural history and long-term clinical outcomes of this new clinical subgroup. Understanding these factors is vital to the development of management guidelines that will lead to the best possible ou ....Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. A new clinical subgroup of HCM patients who are essentially gene carriers, referred to as "Genotype Positive Phenotype Negative" has arisen as a result of genetic testing in at-risk family relatives. Little is known about the natural history and long-term clinical outcomes of this new clinical subgroup. Understanding these factors is vital to the development of management guidelines that will lead to the best possible outcome for these patients.Read moreRead less
The Unfolded Protein Stress Response In Inherited Skeletal Disease: Mechanism And Therapeutic Strategies
Funder
National Health and Medical Research Council
Funding Amount
$549,092.00
Summary
In genetic diseases, gene mutations commonly cause proteins to fold abnormally. This can cause cell stress resulting in cell death. Our studies will determine the role of cell stress in a clinically important group of skeletal diseases caused by collagen mutations. We will also test how we can use small chemicals to alleviate the damage done to the cells by the misfolded proteins, in the hope that this approach will provide new therapeutic strategies for these disorders.
Regulation Of RyR2 Channels By Calmodulin In Healthy And Diseased Hearts
Funder
National Health and Medical Research Council
Funding Amount
$614,421.00
Summary
In the heart, RyR2 is responsible for intracellular Ca2+ release. The RyR2 is comprised of a Ca2+ channel and accessory proteins such as CaM that regulate channel activity. Evidence suggests that RyR2 regulation by CaM is altered in heart failure and human arrhythmia syndromes, but there has been no direct evidence for this. We will provide this direct evidence plus determine how CaM regulates RyR2 channels and intracellular Ca2+ release and how this leads to cardiac arrhythmias.
CCR4/NOT Complex Is A Conserved Regulator Of Heart Function
Funder
National Health and Medical Research Council
Funding Amount
$467,567.00
Summary
Cardiovascular diseases kill an Australian every 11 minutes. The goal of this proposal is to characterize the role of the conserved heart regulators in cardiac function and disease. Our combined multi-species and informatics approach has identified a major disease locus for sudden cardiac death in humans, which we propose to characterize. This work can lead to new classes of drugs to improve cardiac health and also aid in early diagnosis of patients susceptible to sudden cardiac death.
Surgical Management Of The Pulmonary Circulation In Children
Funder
National Health and Medical Research Council
Funding Amount
$114,328.00
Summary
Congenital disorders of the lung circulation are rare. These children often present during infancy with symptoms of heart failure and require surgery to correct these defects. Without surgery, the prognosis of these conditions are poor. Our understanding of these conditions are limited. The proposed study aims to review all patients who underwent surgical repair of abnormalities of lung arteries and veins at the Royal Children’s Hospital.
Atrial Fibrillation And Hypertension: Reverse Cardiac Remodelling Post Renal Denervation
Funder
National Health and Medical Research Council
Funding Amount
$90,144.00
Summary
Patients with hypertension are at increased risk of heart rhythm disorders, yet little is known if treatment of high blood pressure will improve abnormal rhythm. Renal denervation is a new and effective treatment for severe hypertension; this study will assess the adverse changes in heart structure and function due to severe hypertension, and investigate whether renal denervation can ameliorate these changes on a structural and electrical level.
Genetic Predisposition To Abnormal Atrial Substrate In Atrial Fibrillation (GENE-AF Study)
Funder
National Health and Medical Research Council
Funding Amount
$100,531.00
Summary
Atrial fibrillation (AF) is the most common heart rhythm disorder worldwide and its incidence is growing. Our world-first research aims to demonstrate that individuals who carry specific genetic variants are more likely to develop abnormal electrical and structural changes in the heart, which predispose to AF. In doing so, we intend to find the link between genetics and AF, paving the way for research into novel targeted therapies to better manage this complex and difficult to treat disease.