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
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.
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
Towards A New Normokalemic Arrest Paradigm For Orthotopic Heart Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$489,634.00
Summary
Innovations from Nature to Heart Transplantation:a Real Heart Stopper Heart preservation is limited to 4-6 hours of cold-ischaemic storage (0 to 4 C). The risk of post-transplant death doubles if the donor heart is stored from 1 to 5 hours, and triples with 7 hrs storage times. We have developed a new preservation solution borrowing from natural hibernators that will permit organs to be safely stored for up to 15 hours, and offering new opportunities to organ donors and recipients worldwide.
Iron And Oxidative Stress In Stable And Unstable Coronary Artery Disease
Funder
National Health and Medical Research Council
Funding Amount
$86,570.00
Summary
This PhD investigates the key roles iron and insufficient antioxidants play in worsening tissue injury during and following a heart attack, in precipitating blockages in heart arteries, and in impairing blood vessel function in those with heart disease. By using drugs to remove iron from the body, it is possible to compare the detrimental effects of iron (on tissue injury and blood vessel function) in the group treated with the medication and the group treated with placebo.
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
Identification Of A Plasma Factor Of Remote Ischemic Preconditioning And Its Effect On The Proteome After Heart Surgery
Funder
National Health and Medical Research Council
Funding Amount
$385,197.00
Summary
Heart surgery with the heart placed into arrest causes inflammation and tissue damage due to interrupted circulation. We know that prior brief interruption and restoration of blood supply called remote ischemic preconditioning (IPC) can protect heart and lungs against damage. Our previous studies indicate that IPC involves a circulating factor that protects the tissue by optimizing energy preservation. This knowledge can be applied to organ transplants, protection from stroke and heart attack.
Role Of Osteopontin In Ischemic-like Injury To The Retina
Funder
National Health and Medical Research Council
Funding Amount
$357,862.00
Summary
The molecule osteopontin (OPN) is implicated in the response of certain tissues to disease. We have new evidence that the level of OPN in the visual retina increases markedly following injury. We hypothesise that OPN is produced by specialised retinal cells in response to injury and functions to promote the survival of nerve cells. The proposed research seeks to investigate this hypothesis and the results will contribute to a greater understanding of the role of OPN in retinal diseases.
Targeting Innate Immunity To Prevent Chronic Dysfunction Of The Transplanted Kidney
Funder
National Health and Medical Research Council
Funding Amount
$497,057.00
Summary
Kidney transplantation is the optimal treatment for patients suffering from end-stage kidney disease. Chronic transplant dysfunction is the major barrier to long-term health after transplantation, and is the subject of this application. Our studies suggest a signaling system activates immunity and leads to chronic transplant dysfunction. We aim to block this signaling system in mouse models to identify clinically applicable treatments to prevent kidney transplant failure.
Identification Of Mechanisms By Which Mesenchymal Stromal Cells Ameliorate Renal Ischaemia Reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$104,985.00
Summary
Acute kidney injury (AKI) is a common clinical entity which is associated with an increased risk of death and chronic kidney disease. Infusing adult mesenchymal stromal cells (cells which usually reside in the bone marrow but migrate to sites of inflammation or injury) has been shown to be beneficial in animal models of AKI, but it is not known how they have this effect. This project is designed to investigate the mechanism of action of mesenchymal stromal cells in AKI.