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
This project studies the mechanisms involved in rejection of skin and heart grafts using a novel model to track the behaviour of individual graft-reactive white blood cells. We will test two promising new techniques to limit graft rejection: using drugs to inhibit the entry of graft-reactive cells into the graft, and administering cells with the ability to suppress the function of graft-reactive cells. This work will help us to design new therapies to prevent heart graft rejection.
Cardiac Dysfunction In Advanced Liver Disease And After Liver Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$128,224.00
Summary
Heart disease is the leading cause of early death after liver transplantation (LT). The scarcity of donor organs means that LT is a limited and valuable resource. We propose screening for heart disease before LT by CT scanning of heart arteries and heart function on stress testing to improve detection of coronary heart disease (CHD). Follow-up CT scans will also assess if LT causes progression of CHD. These studies will aid in development of personalised treatment strategies to improve outcomes.
The Cellular Origin And Nuclear Signaling Mechanisms Of Cardiac Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$383,893.00
Summary
Stem cells have special characteristics; they are able to be grown quickly and they have the potential to turn into different types of cell. These two characteristics indicate the potential to use these cells to repair diseased organs. Heart disease is an ideal area to investigate the use of such cell-based therapy options. This is because a weakened heart muscle is very common (especially as we age) and because without assistance, the body is not able to repair a weakened heart.
Development Of A First-in-class Therapeutic For Protecting The Ischemic Heart
Funder
National Health and Medical Research Council
Funding Amount
$926,673.00
Summary
Heart disease is the leading cause of death globally. Heart attacks are the primary cause of death associated with heart disease. We have discovered a drug, Hi1a, that blocks the injury response of the heart when a heart attack happens. There are no other drugs currently available or in the discovery pipeline that address this problem. This proposal will use models of injury to the heart as well as safety studies to help develop Hi1a as a new drug for people who suffer from heart attacks.
Investigation Of Cardiac Stem Cell Regenerative Capabilities And Their Enhancement By Manipulation Of Telomerase Reverse Transcriptase
Funder
National Health and Medical Research Council
Funding Amount
$491,462.00
Summary
Heart failure rates are increasing exponentially in Australia and worldwide. One in two people diagnosed with severe heart failure will die within one year of diagnosis. This burden of heart failure is underpinned by the heart’s limited capacity for self-repair after injury. This limitation could be overcome by stimulating newly discovered stem cell populations residing within the adult heart itself. This project investigates ways to harness and enhance the power of these stem cells.
Regulation Of The Cardiac Sodium/proton Exchanger During Ischaemia, Reperfusion And Preconditioning
Funder
National Health and Medical Research Council
Funding Amount
$101,000.00
Summary
Heart attacks are currently treated with drugs to dissolve the clot in the coronary artery or by catheterisation with the aim of restoring blood flow to the ischaemic heart muscle. If restoration of blood flow occurs soon after the heart attack, the ischaemic region can recover completely. However if treatment is delayed, the ischaemic region may not recover. This project concerns the mechanisms that are involved in the myocardial damage which occurs after moderate periods of ischaemia. A transp ....Heart attacks are currently treated with drugs to dissolve the clot in the coronary artery or by catheterisation with the aim of restoring blood flow to the ischaemic heart muscle. If restoration of blood flow occurs soon after the heart attack, the ischaemic region can recover completely. However if treatment is delayed, the ischaemic region may not recover. This project concerns the mechanisms that are involved in the myocardial damage which occurs after moderate periods of ischaemia. A transport protein, the sodium-proton exchanger, is involved in recovery and if its action is blocked with an inhibitory drug, recovery of the ischaemic myocardium is improved. However clinical trials of the drug in humans have given variable results. We are investigating the regulation of this exchanger and believe that such information is essential to the efficient use of the inhibitory drugs in humans and may identify other pathways to improving recovery after ischaemia.Read moreRead less
Finding New Evidence Based Therapies For Treating Heart Disease And Stimulating Regeneration
Funder
National Health and Medical Research Council
Funding Amount
$11,088,182.00
Summary
Heart disease is the leading cause of death and disability in our society. This interactive team of clinicians and basic scientists will exploit the latest advances in genome technology and stem cell biology to gain greater insights into the genetic basis of heart disease, elucidate the molecular mechanisms of cardiac function and disease and translate these insights into the development of novel therapeutic approaches for the prevention and treatment of heart disease.
CD39 Protects Against Renal Ischaemic-reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$441,584.00
Summary
In many medical settings, such as heart attacks, strokes, transplantation, heart surgery, shock and infection, the blood supply to an organ may be compromised resulting in damage. The cessation of blood flow depletes the organ of oxygen and generates a number of toxic changes. Re-establishing blood flow to the organ is essential to prevent further damage, however the reestablishment of blood flow itself can be harmful to the organ. The return of blood flow, oxygen and energy can actually promote ....In many medical settings, such as heart attacks, strokes, transplantation, heart surgery, shock and infection, the blood supply to an organ may be compromised resulting in damage. The cessation of blood flow depletes the organ of oxygen and generates a number of toxic changes. Re-establishing blood flow to the organ is essential to prevent further damage, however the reestablishment of blood flow itself can be harmful to the organ. The return of blood flow, oxygen and energy can actually promote more widespread injury - a process known as ischaemia-reperfusion injury (IRI). A greater understanding of IRI should aid in the development of drugs that minimise its impact. The overall aim of this work is to examine the role of a molecule - CD39 - in IRI. This molecule is ideally situated to minimise injury - it is located on cells that line blood vessels and, as such, is able to directly neutralise toxins released in response to this injury. We, therefore, believe that it will be protective in this setting. We have developed animals that express this molecule and have preliminary results to suggest that these animals are protected in experimental models of IRI as well as in several other models including heart transplantation surgery; processes that share many features with IRI. Moreover, mice deplete of this molecule are prone to more severe IRI. We aim to investigate this by using animals both lacking and expressing CD39. Blood flow to the kidneys will be interrupted for 30 minutes and kidney function assessed at 24 and 48 hours. We will then delve into the potential mechanisms underpinning IRI by determining whether the kidney itself or the blood cells afford protection, which has direct clinical implications.Read moreRead less
Intravascular Coagulopathy In Discordant Xenotransplantation
Funder
National Health and Medical Research Council
Funding Amount
$447,750.00
Summary
The successful treatment of many conditions in which the relevant organ has failed completely and irreversibly is to replace that organ with a new one ie. to perform a transplant. It is well known that there are far fewer organs available for transplantation than the number needed. This means that for those conditions where a supportive treatment is available, eg. the artificial kidney, patients must be maintained by that method, however for other organs such as hearts, lungs and livers, there i ....The successful treatment of many conditions in which the relevant organ has failed completely and irreversibly is to replace that organ with a new one ie. to perform a transplant. It is well known that there are far fewer organs available for transplantation than the number needed. This means that for those conditions where a supportive treatment is available, eg. the artificial kidney, patients must be maintained by that method, however for other organs such as hearts, lungs and livers, there is no mechanical substitute. If these patients do not receive a transplant, they die. A solution to this problem is to use organs from animals. This is called xenotransplantation. The pig is the most suitable donor, however despite many similarities to humans which make it suitable, there are many differences which are still to be overcome before clinical application is possible. These differences are at a very fine molecular level and prevent the normal integration of the organ into the new recipient. The result is that the new organ is rejected within minutes. This process is called hyperacute rejection and by research into its mechanism it was found to be due to just a few differences. We and others have genetically modified pigs so that they have the human components and this has completely prevented this form of rejection. However,we have found a second barrier which causes a rejection response after a few days. It is now known that a major component of the cause of this second barrier is a few differences in the clotting system. We propose to make further genetic modifications which we think will prevent this rejection. This project proposes to examine various genetic modifications and test their effect in small animal models before going on to make and test pigs in which human anti-clotting genes have been inserted. . If we are successful, the possibility of replacing failed human organs with animal organs will be a step closer.Read moreRead less