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
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
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
Improving Muscle Function After Injury: Novel Tissue Engineering Strategies For Exercise, Surgery And Sports Medicine
Funder
National Health and Medical Research Council
Funding Amount
$288,210.00
Summary
Muscles can be injured by excessive strains when playing sports, in road and workplace accidents, and during plastic and reconstructive surgery. Some surgeries require an unavoidable interruption to the muscle's normal blood supply (called 'ischaemia'). Subsequent return of the muscle's blood supply (reperfusion) is problematic in that a severe secondary muscle injury can ensue mediated by the influx of damaging free radicals when blood flow is restored. Tissue-engineering provides a novel thera ....Muscles can be injured by excessive strains when playing sports, in road and workplace accidents, and during plastic and reconstructive surgery. Some surgeries require an unavoidable interruption to the muscle's normal blood supply (called 'ischaemia'). Subsequent return of the muscle's blood supply (reperfusion) is problematic in that a severe secondary muscle injury can ensue mediated by the influx of damaging free radicals when blood flow is restored. Tissue-engineering provides a novel therapeutic approach to restore muscle structure and function to damaged muscles after injury or disease. Our recent research using controlled release of growth factors from biodegradable hydrogels has exciting application for muscle repairafter injury. We will utilize these cutting edge tissue engineering strategies to deliver to damaged muscles a hydrogel containing controlled delivery (slow release) microcapsules loaded with an anabolic agent (the beta-agonist, formoterol) and-or a growth factor (IL-15) designed to enhance functional muscle repair after three distinct but clinically relevant models of muscle injury: a) crush injury: A model for muscle injuries on the sports field, in the workplace, and those associated with road trauma; b) ischaemia-reperfusion injury: a model for muscle damage associated with surgical interventions, muscle transfers for functional restoration, and other injuries associated with plastic and reconstructive surgery; and c) contraction-induced injury: a model for strain injuries such as hamstring muscle tears that can occur on the sports field. After injury we will assess functional muscle repair using a comprehensive series of histological, biochemical, molecular, immunochistochemical, and physiological techniques. The research has broad application to exercise and clinical medicine; including sports, emergency and rehabilitation medicine, and plastic, reconstructive, and orthopaedic surgery.Read moreRead less
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
Enhancing The Neuroprotective Benefit Of Hypothermia With Melatonin In The Asphyxiated Neonate
Funder
National Health and Medical Research Council
Funding Amount
$785,331.00
Summary
During labour, asphyxic episodes which cause a severe reduction in oxygen supply can become prolonged and result in perinatal brain injury, termed Hypoxic Ischemic Encephalopathy, which may underlie cerebral palsy. Presently, newborn infants with suspected encephalopathy are cooled, which modestly protects the brain against cellular injury. We propose that the administration of melatonin to the newborn, in addition to cooling, will decrease the post-asphyxic formation of oxygen free radicals, th ....During labour, asphyxic episodes which cause a severe reduction in oxygen supply can become prolonged and result in perinatal brain injury, termed Hypoxic Ischemic Encephalopathy, which may underlie cerebral palsy. Presently, newborn infants with suspected encephalopathy are cooled, which modestly protects the brain against cellular injury. We propose that the administration of melatonin to the newborn, in addition to cooling, will decrease the post-asphyxic formation of oxygen free radicals, thereby reducing the progression of brain damage.Read moreRead less
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.