Enkephalin Metabolism In Cardiac Ischemia, Heart Failure And Cardiac Surgery
Funder
National Health and Medical Research Council
Funding Amount
$327,037.00
Summary
It has recently been discovered in animal studies that heart muscle can make its own opioid proteins. Previously, it was thought that only nerves made and released opioids. We have recently found that a class of opioids called enkephalins are made and then depleted from the heart during the stress of oxygen and nutrient deprivation. Enkephalins have been found to have potent metabolic effects on the heart. Previous work has shown that opioids can protect the heart against injury incurred during ....It has recently been discovered in animal studies that heart muscle can make its own opioid proteins. Previously, it was thought that only nerves made and released opioids. We have recently found that a class of opioids called enkephalins are made and then depleted from the heart during the stress of oxygen and nutrient deprivation. Enkephalins have been found to have potent metabolic effects on the heart. Previous work has shown that opioids can protect the heart against injury incurred during disease that restricts energy and oxygen supply to the blood vessels and heart. We wish to demonstrate this for the first time in human heart, and we will explore whether the production of enkephalins is altered by the stresses of cardiac surgery and heart failure. Understanding how the human heart attempts to protect itself in disease and how enkephalins work under these conditions, may prove valuable in the development of new drug therapy with synthetic drugs which mimic the action of enkephalins for heart protection during cardiac surgery, heart transplantation and ischemic heart disease. We will test whether specific enkephalins may be used to improve donor heart viability for transplantation by improving the duration and quality of preservation during storage. Understanding what happens to enkephalin production and metabolism in the failing hearts of patients may allow us to find new therapeutic targets in heart failure.Read moreRead less
Preconditioning: The Molecular Basis For Protection From Hepatic Ischemia-reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$406,980.00
Summary
When the blood supply to the liver is cut off temporarily (ischemia) and later restored (reperfusion) the liver is damaged by a process called ischemia-reperfusion (IR) injury. This is a major problem during liver surgery and is also an underlying problem in liver transplantation; following storage of a donor liver ready for placing into the recipient it can undergo a similar process called preservation injury. We now understand a lot about how IR comes about, particularly by the formation of da ....When the blood supply to the liver is cut off temporarily (ischemia) and later restored (reperfusion) the liver is damaged by a process called ischemia-reperfusion (IR) injury. This is a major problem during liver surgery and is also an underlying problem in liver transplantation; following storage of a donor liver ready for placing into the recipient it can undergo a similar process called preservation injury. We now understand a lot about how IR comes about, particularly by the formation of damaging oxygen radicals within liver cells to start a process of programmed cell death, but it remains difficult to prevent or treat IR injury. A recent breakthrough has been recognition that subjecting the liver to only a short period (5 or 10 minutes) of ischemia protects against a later period of prolonged ischemia or IR. In the investigator s mouse model, for example, such preconditioning was 60 to 90% protective (depending on the time after IR). This project seeks to understand how preconditioning works to protect the liver against IR injury. Our idea is that preconditioning generates a limited amount of oxygen radicals, and that these turn on signalling pathways in the cell that regulate certain protective genes. Genes that encode antioxidant and other anti-stress pathways are likely to be important, but so are genes that prepare the cell to enter the cell cycle and divide into new cells that regenerate the liver. Conversely, genes that program cell death may be turned off. The outcomes of this research will be to understand the molecular and cellular basis of how preconditioning protects against ischemia-reperfusion injury of the liver. This will allow drug treatments to be devised that, by simulating preconditioning, prevent this common and severe type of liver damage.Read moreRead less
Activin A And Follistatin Are Potential Key Regulators Of Organ Transplant Dysfunction And Graft Survival.
Funder
National Health and Medical Research Council
Funding Amount
$535,579.00
Summary
The grant examines novel key regulators in organ transplantation. It examines molecules that are released during transplant surgery and on the return of blood flow to the organ which can cause inflammation and scarring. The release is increased by heparin, an anticoagulant used in organ preparation. Alternative anticoagulants and blockers of the regulators released will be tested to prevent the damage to the transplant, potentially improving both the short and long term graft survival and functi ....The grant examines novel key regulators in organ transplantation. It examines molecules that are released during transplant surgery and on the return of blood flow to the organ which can cause inflammation and scarring. The release is increased by heparin, an anticoagulant used in organ preparation. Alternative anticoagulants and blockers of the regulators released will be tested to prevent the damage to the transplant, potentially improving both the short and long term graft survival and function.Read moreRead less
Outcomes Of The Arterial Switch Operation: A Multi-centre Study
Funder
National Health and Medical Research Council
Funding Amount
$86,733.00
Summary
The arterial switch operation is the surgery of choice for children born with transposition of the great arteries, a congenital heart defect where the main two vessels of the heart arise from wrong pumping chambers of the heart. There are very few studies looking at adults after this operation. We aim to study all patients who have had an arterial switch. The results of this study will further increase our knowledge of the long term consequences of having the arterial switch operation.
THE ROLE OF RESIDENT MAST CELLS IN ISCHAEMIA-REPERFUSION INJURY OF SKELETAL MUSCLE.
Funder
National Health and Medical Research Council
Funding Amount
$226,320.00
Summary
NHMRC 209113 LAY DESCRIPTION Ischaemia reperfusion injury occurs in skeletal muscle when the blood-oxygen supply is cut off (ischaemia) and later restored (reperfusion). If the duration of ischaemia is short some of the muscle survives. However, when blood flow and oxygen are restored the muscle is subjected to more injury, which is thought to be caused by oxygen and-or white blood cells. This type of injury occurs in muscle which has been crushed, limbs that have been broken or traumatized, in ....NHMRC 209113 LAY DESCRIPTION Ischaemia reperfusion injury occurs in skeletal muscle when the blood-oxygen supply is cut off (ischaemia) and later restored (reperfusion). If the duration of ischaemia is short some of the muscle survives. However, when blood flow and oxygen are restored the muscle is subjected to more injury, which is thought to be caused by oxygen and-or white blood cells. This type of injury occurs in muscle which has been crushed, limbs that have been broken or traumatized, in replantation of amputated parts, in transplantation, after some surgical procedures and after microsurgical transfer of muscle. Once established there is no effective treatment. Our experiments show that a particular cell, the mast cell, and a particular molecule, nitric oxide, are involved in causing ischaemia reperfusion injury. However, the extent of their involvement is unknown. In this proposal we will investigate the effect of replacing mast cells into muscles, in a unique variety of mice which normally don t contain mast cells and are resistant to ischaemia reperfusion injury. In one group of mice we will put back normal mast cells and in a second group of mice we will put back mast cells that cannot produce the nitric oxide molecule. These experiments will determine, unambiguously, the extent of involvement of mast cells and mast cell-derived nitric oxide. In the second part of this proposal will carry out a time course study, using pharmacologically induced mast cell degranulation, to determine when the mast cells become injurious to skeletal muscle. These experiments will identify the period during which mast cell behaviour can be modulated in order to protect the muscle from ischaemia reperfusion injury. Determination of the role of mast cells, and an understanding of the timing during which they become injurious would provide a logical basis for optimizing drug therapy in clinical applications of these findings.Read moreRead less
Clinical Feasibility Study Of Omega-3 PUFA Therapy For The Reduction Of Post-cardiac Surgery Atrial Arrhythmias
Funder
National Health and Medical Research Council
Funding Amount
$442,092.00
Summary
The aim of this study is to determine the molecular and clinical impact of omega-3 polyunsaturated fatty acids (PUFA) pre-treatment 2 weeks before cardiac surgery in 150 patients. The outcome of this proposal will indicate proof of molecular concepts, clinical feasibility and specific design elements of a future, large scale, placebo controlled, prospective randomised trial of oral therapy with omega-3 polyunsaturated fatty acids (PUFA). Recently, omega-3 PUFA via fish diet was reported to be li ....The aim of this study is to determine the molecular and clinical impact of omega-3 polyunsaturated fatty acids (PUFA) pre-treatment 2 weeks before cardiac surgery in 150 patients. The outcome of this proposal will indicate proof of molecular concepts, clinical feasibility and specific design elements of a future, large scale, placebo controlled, prospective randomised trial of oral therapy with omega-3 polyunsaturated fatty acids (PUFA). Recently, omega-3 PUFA via fish diet was reported to be linked to low incidence of AF. The main aim is to provide a cheap and safe preventative therapy against post-operative atrial fibrillation (AF), a key heart rhythm disorder that occurs in at least 1 in 4 patients after heart surgery and increases post-operative complications, limits recovery and increases hospital stay and cost. Biochemical study elements are important to gain valuable insight into the molecular mechanisms (directly in human heart) that underlie post-operative heart rhythm disorder and may delineate new more precise molecular targets for therapy. No previous clinical study has ever examined whether omega-3 PUFA therapy prevents post-operative heart rhythm disorder. Use of 3g-day omega-3 PUFA pre-treatment in the surgical setting has been shown to be safe in a number of small studies, including our own. Our preliminary data indicates that therapy increases heart and blood content of omega-3 PUFA ~2-fold, and reduces the incidence of AF. Post-operative AF is an expensive resource burden in all cardiothoracic surgery units of Australian hospitals and targets key health priorities. Due to the non-patentable nature of omega-3 PUFA, significant industry based support for clinical research is limited. A positive outcome would rapidly pave the way for widespread use in elective surgery. Reduced length of hospital stay, cost-savings, and the increase in productivity as healthy individuals return to their communities would nationally repay the investment many fold.Read moreRead less