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.
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
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
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
Identification Of A New Thrombosis Mechanism Triggered By Dying Platelets
Funder
National Health and Medical Research Council
Funding Amount
$608,742.00
Summary
A severe reduction in blood flow (ischemia) to the intestines can trigger blood clot formation (thrombosis) in multiple organs, including the lungs. We have identified a new thrombosis mechanism that is triggered by the clumping of white blood cells in the intestines, leading to widespread thrombosis in the lung. Here we will investigate the mechanisms triggering this thrombosis mechanism with the ultimate aim of identifying more effective antithrombotic approaches.
The Role Of Tissue Factor In Renal Ischaemia-Reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$268,500.00
Summary
Reestablishment of blood flow to an organ (reperfusion) following temporary cessation or obstruction is essential for survival and recovery of the organ. However while essential for organ survival reperfusion results in damage to the organ in a number of cases, including heart, brain, kidney, and gastrointestinal tract, with important implications for patient morbidity and mortality. In the kidney lack of blood flow can result in acute kidney failure that is a costly condition to manage often re ....Reestablishment of blood flow to an organ (reperfusion) following temporary cessation or obstruction is essential for survival and recovery of the organ. However while essential for organ survival reperfusion results in damage to the organ in a number of cases, including heart, brain, kidney, and gastrointestinal tract, with important implications for patient morbidity and mortality. In the kidney lack of blood flow can result in acute kidney failure that is a costly condition to manage often requiring admission to an intensive care unit and is still associated with a significant risk of death. Reperfusion injury that occurs during renal transplantation is currently thought to be an important contributor to delayed establishment of kidney function following transplantation that in turn may increase the incidence of acute and chronic rejection. The studies outlined in this proposal will investigate how molecules involved in the blood clotting system may contribute to the inflammatory response that occurs upon reperfusion of the kidney following prior obstruction of blood flow. We will study a mouse model of kidney reperfusion injury and using genetically modified mice determine the role of various blood clotting-related proteins in subsequent inflammation and organ damage. The approach to be employed will provide a powerful method to determine the role of various molecules and pathways in contributing to kidney damage after reperfusion injury. Interventions that may reduce the incidence or severity of renal damage following kidney reperfusion injury have the potential to be of major benefit to patients and to reduce health care costs.Read moreRead less
Optimizing Stroke Therapy - Advanced Brain Imaging And Reperfusion Therapies
Funder
National Health and Medical Research Council
Funding Amount
$419,180.00
Summary
Most stroke is due to a blocked blood vessel reducing blood flow to the brain. This research aims to optimize fast restoration of blood flow to the brain and improve patient outcomes. We will test potentially more effective clot-dissolving medication, examine potential benefits of redesigning pre-hospital ambulance transport systems and clarify the role of advanced brain imaging to maximize delivery of recently proven minimally invasive procedures to physically remove blood clots in the brain.