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The Role Of Aquaporins In Cardiac Ischaemia And Reperfusion
Funder
National Health and Medical Research Council
Funding Amount
$412,670.00
Summary
We are studying the important clinical problem of why the heart doesn't work very well after it has been deprived of blood. This may occur during a heart attack due to coronary artery disease and during cardiac surgery when the heart is stopped. The problem affects children as well as adults undergoing surgery. The reason the heart doesn't work well is related to energy supply and tissue damage caused during the shortage of blood supply and the period soon after flow is restored. Until the heart ....We are studying the important clinical problem of why the heart doesn't work very well after it has been deprived of blood. This may occur during a heart attack due to coronary artery disease and during cardiac surgery when the heart is stopped. The problem affects children as well as adults undergoing surgery. The reason the heart doesn't work well is related to energy supply and tissue damage caused during the shortage of blood supply and the period soon after flow is restored. Until the heart recovers, inadequate pump function may cause low blood flow problems downstream in vital organs such as the brain and kidneys. Under the microscope, a common feature of affected hearts is swelling of the cells and of the energy producing parts called mitochondria. We have identified, for the first time, unique proteins that allow water to move into and around cells of the heart. These proteins are called 'aquaporins' and early results suggest they are involved in how mitochondria deal with a shortage of blood supply. Interestingly, aquaporins are also affected in diseases that affect muscle strength, and we are using what is known in these diseases to further study the role of aquaporins in the heart. Our experiments to will test heart function from the level of the cell, all the way up to the whole heart. To improve the power of our experiments, we are working with mice that lack the special water transport proteins, as a prelude to developing drug therapy for this important problem. By manipulating aquaporin levels or function, we plan to improve heart preservation during periods of no blood flow, and after surgery. This would importantly reduce the risks associated with heart attack and cardiac surgery by avoiding complications associated with poor pump function.Read moreRead less
Role Of Microparticles In Cardiac Ischemia Reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$55,575.00
Summary
Interventional cardiology has reduced the mortality rate associated with heart attack, unfortunately the prevalence of heart failure has subsequently increased, caused in part by reperfusion injury of previously occluded vessels. We aim to identify novel insights into the pathogenesis of IR injury in the heart, as well as the development of new approaches to prevent cardiac damage during cardiac surgery, transplantation, post-angioplasty and coronary artery stenting.
Reduced Ischaemic Tolerance In The Aged Myocardium: The Role Of Adenosine And Adenosine Receptors
Funder
National Health and Medical Research Council
Funding Amount
$470,250.00
Summary
Despite a decline in deaths rates due to heart disease over the last decade, cardiovascular disease remains the single greatest cause of premature death in individuals over 65 years of age. It accounts for a major and increasing portion of health care costs. Coronary artery disease affects 50% of those older than 65, and with the ageing of our population it is estimated that the elderly population will nearly double from 13-14% to 25% over the next 30 years. Unfortunately, it appears that the ag ....Despite a decline in deaths rates due to heart disease over the last decade, cardiovascular disease remains the single greatest cause of premature death in individuals over 65 years of age. It accounts for a major and increasing portion of health care costs. Coronary artery disease affects 50% of those older than 65, and with the ageing of our population it is estimated that the elderly population will nearly double from 13-14% to 25% over the next 30 years. Unfortunately, it appears that the aged heart is less resistant to disease and injury, contributing to the increase in mortality with ageing. The reasons are not known. This research project will attempt to identify molecular changes which occur in the heart during ageing which may lead to a decline in ability to withstand disease and injury. The research will specifically examine the possibility that a key protective response, known as the adenosine receptor system, is somehow impaired or abnormal in the cells of the aged heart. If it is found that this process is impaired, the research will attempt to rectify this abnormality using new genetic therapy techniques to switch on the heart's own intrinsic defense mechanisms. This may ultimately open up new avenues for specific therapeutic approaches to treatment of ischaemic heart disease in the elderly.Read moreRead less
Adenosine A1 And A3 Receptor Mediated Cardioprotection In Ischaemic Myocardium
Funder
National Health and Medical Research Council
Funding Amount
$265,698.00
Summary
Damage to the heart from coronary vascular disease causes significant morbidity and mortality in Australia. Indeed, ischaemic injury represents the single greatest cause of premature death. Moreover, due to the increasing age of our population the problem is growing - coronary artery disease affects 50% of those older than 65, contributing to an increased incidence of angina pectoris, myocardial infarction, arrhythmia, congestive heart failure, and sudden death. Protective strategies have been, ....Damage to the heart from coronary vascular disease causes significant morbidity and mortality in Australia. Indeed, ischaemic injury represents the single greatest cause of premature death. Moreover, due to the increasing age of our population the problem is growing - coronary artery disease affects 50% of those older than 65, contributing to an increased incidence of angina pectoris, myocardial infarction, arrhythmia, congestive heart failure, and sudden death. Protective strategies have been, and continue to be, developed to reduce the extent of tissue damage and minimise prolonged reductions in heart function. The success of these interventions has been mixed. This research project takes the novel approach of identifying the true roles of two receptors present in the heart (the adenosine A1 and A3 receptors) which may play a crucial role in enhancing tolerance of the heart to disease and injury. We currently do not fully understand the roles of these receptors, although preliminary findings suggest they can exert powerful protective effects during disease conditions. From a fundamental viewpoint, identifying the roles of these two receptors will significantly advance our understanding of the mechanisms of injury and protection in the heart. From a therapeutic viewpoint, this study will take us closer to the potential use of adenosine receptor-based therapy in protecting the heart from ischaemic injury.Read moreRead less
I am a cardiac pharmacologist investigating new therapies for the precursors of, and preventing their transition to, heart failure. My core activities focus on factors that control cardiac hypertrophy and ventricular function, in both the absence and pres
A Temporal Profile Of Signaling Via Phosphorylation During Myocardial Ischemia - Reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$369,641.00
Summary
Cardiovascular disease (CVD) is the major cause of death in Australians and sequelae post-myocardial ischemia - reperfusion (I-R) are responsible for the greatest proportion of CVD-related mortality. Despite this burden, there is little known of the molecular events that mediate I-R. This project will utilize cutting-edge technology to elucidate the molecular signaling events that lead to I-R injury, as well as determine the basis for protection afforded by clinical pre- and post-conditioning.
Activated Platelets As Unique Targets For Early Imaging And Site-directed Therapy Of Cardiovascular And Inflammatory Diseases
Funder
National Health and Medical Research Council
Funding Amount
$846,979.00
Summary
Heart attack and inflammatory diseases such as rheumatoid arthritis und multiple sclerosis either kill or severely disable people. We use the presence of platelets early on in these diseases to develop methods for early diagnosis as well as potential drugs for site-directed therapy. We have developed new biotechnological tools to perform novel high sensitivity imaging in Positron Emission Tomography (PET) and laser light imaging as well as a localised anti-inflammatory therapy.
C-JUN TARGETING STRATEGIES AS NOVEL CARDIOPROTECTIVE AGENTS IN ISCHAEMIA-REPERFUSION INJURY
Funder
National Health and Medical Research Council
Funding Amount
$361,148.00
Summary
Acute myocardial infarction (AMI) and its sequelae are an increasing problem in terms of morbidity, mortality and healthcare costs in Australia and the industrialised world; in the USA this is estimated annually at 900,000 and 225,000 patients and US$60 billion, respectively. Current treatment for AMI includes mechanical (percutaneous coronary intervention) or thrombolytic therapy; however, these approaches are directed primarily at epicardial arteries rather than the myocardium and are, therefo ....Acute myocardial infarction (AMI) and its sequelae are an increasing problem in terms of morbidity, mortality and healthcare costs in Australia and the industrialised world; in the USA this is estimated annually at 900,000 and 225,000 patients and US$60 billion, respectively. Current treatment for AMI includes mechanical (percutaneous coronary intervention) or thrombolytic therapy; however, these approaches are directed primarily at epicardial arteries rather than the myocardium and are, therefore, suboptimal. Strategies aimed at directly protecting cardiomyocytes from ischaemia-reperfusion injury, reducing leukocyte recruitment and myocardial cell death, would complement current approaches restoring epicardial artery flow and are keenly sought. This project will demonstrate the capacity of two separate gene-silencing strategies (DNAzymes and siRNA to suppress the expression of the immediate-early gene, c-Jun in cardiomyocytes and reduce infarct size, left ventricular dysfunction, apoptosis, inflammation, production of reactive oxygen species, angiogenesis and fibrosis in the injured rat myocardium. It will also shed light on the molecular mechanisms underlying c-Jun-mediated myocardial inflammation. As such, these studies will provide important proof of principle evidence for these small molecule nucleic acid agents as potential therapeutic tools as cardioprotective agents in ischaemia-reperfusion injury.Read moreRead less
Therapeutic Silencing Of Egr-1 By Novel Catalytic Oligodeoxynucleotides For The Treatment Of Acute Myocardial Infarction
Funder
National Health and Medical Research Council
Funding Amount
$384,353.00
Summary
Heart attack remains a major health problem. We have identified a gene in the heart which is turned on in the first few hours of a heart attack. We have shown in principle that switching this gene off using a novel synthetic drug, reduces heart attack size. Our project assesses the long term effects of this drug on the heart using state of the art imaging when the the drug is administered in a clinically relevant manner. This study may faciliate a new treatment approach for this condition.
The Role Of C-reactive Protein (CRP) In Localising Inflammation To Misfolded Proteins And “stressed” Cells: A Basis For The Development Of New Anti-inflammatory Reagents?
Funder
National Health and Medical Research Council
Funding Amount
$723,488.00
Summary
Many diseases are exacerbated by inflammatory reactions. We describe how a protein circulating in the blood is a major driver of inflammatory reactions and how it is transformed from an inactive state to an active, highly pro-inflammatory state. Our project aims to understand how this transformation occurs at the molecular level, and to develop diagnostic techniques and innovative drugs to treat diseases such as heart attack, Alzheimer’s disease and other inflammatory diseases.