Human RIPC-derived Regulatory Molecules For Cardioprotection Against Ischemic And Cardiopulmonary Bypass Injury
Funder
National Health and Medical Research Council
Funding Amount
$642,083.00
Summary
Our previous work indicates that evoked human blood borne factors confer protection against injury, due to loss of blood flow in heart muscle, when a brief stress is remotely applied to a limb (remote ischemic preconditioning). We have identified these proteins that appear to activate genetic and metabolic regulation of adaptive cell survival processes. We will now test their individual and combined capacity, efficiency and mechanisms of protection in the heart using cell and clinical models.
Upscaling Cardiac Tissue Engineering: Differentiation Of IPS Cells, Enrichment And Bionic Approaches
Funder
National Health and Medical Research Council
Funding Amount
$709,758.00
Summary
Stem cell therapies to repair heart muscle are experimental methods which promise future clinical treatments. Our tissue engineering chamber model provides a protective environment for implanted cells and generates contracting heart tissue. Towards clinical application we will scale up the tissue volume produced by: improving cell supply with new stem cell technologies, design chambers for bulk cell implantation, adopt a bionic approach to cell pacing and apply the model into larger animals.
Enhancing The Cardioprotective Effect Of Diadenosine Tetraphosphate: Designing Inhibitors Against Ap4A Hydrolase
Funder
National Health and Medical Research Council
Funding Amount
$442,500.00
Summary
Ischemia describes the condition where blood flow in the blood vessels of the heart is decreased or blocked, preventing delivery of oxygen and nutrients to the heart. Ischemic preconditioning is a phenomenon where short bursts of ischemia, followed by reperfusion, actually protect the heart from a subsequent longer period of ischemia. The biochemical signalling events involved in preconditioning are complex and incompletely defined, but most likely involve multiple pathways, although the mitocho ....Ischemia describes the condition where blood flow in the blood vessels of the heart is decreased or blocked, preventing delivery of oxygen and nutrients to the heart. Ischemic preconditioning is a phenomenon where short bursts of ischemia, followed by reperfusion, actually protect the heart from a subsequent longer period of ischemia. The biochemical signalling events involved in preconditioning are complex and incompletely defined, but most likely involve multiple pathways, although the mitochondrial ATP-dependent potassium channel may be in common with most pathways. Pretreatment with the compound diadenosine tetraphosphate (Ap4A) mimics ischemic preconditioning with noticeable reductions in tissue necrosis (cell death). This treatment has been shown in experimental work to protect the heart during periods of stress such as in heart surgery or recovery from an ischemic event. The biological site of action by Ap4A may be the mitochondria ATP-dependent potassium channel or an associated protein. Ap4A can be degraded by enzymes located inside and on the outside of heart cells, notably by two forms of Ap4A hydrolase. We will use antibody assays to understand the specific localization and amount of Ap4A hydrolase before and after ischemia and after ischemic preconditioning in human heart muscle and blood vessels. We propose to determine the structure of the enzyme and use novel computer methods to screen databases for potential inhibitors. These inhibitors of Ap4A hydrolase activity could aid the design of a potent inhibitor that would prevent Ap4A hydrolase from degrading Ap4A and therefore enhance the cardioprotective properties of Ap4A as well as minimizing side effects from the break down of Ap4A. We will also use these inhibitors and other known non-degradable Ap4A analogues in bioassays to test the relative significance of Ap4A hydrolase present in different cellular locations.Read moreRead less
Does Remote Ischemic Preconditioning Induce Protective Mitochondrial Function In Congenital Heart Defect Repair Surgery?
Funder
National Health and Medical Research Council
Funding Amount
$142,759.00
Summary
The body's own protective mechanism against injury due to reduced blood flow (ischemic preconditioning) has been studied for over 2 decades, yet the clinical benefits have not been realised until recently . We have previously shown that this innate protection can be induced without drugs in children having heart surgery. We will extend these findings to determine the mechanism of protection, develop a method to monitor this in blood cells and see if this is related to post-operative outcomes.
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
Delayed Phase Of Remote Ischemic Preconditioning: Clinical Application And The Role Of Kallikrein-kinin Pathway.
Funder
National Health and Medical Research Council
Funding Amount
$159,197.00
Summary
Brief episodes of interruption of blood flow to the arm or leg provide strong protection against prolonged interruption of blood flow to a target organ (e.g., heart or lung). This is known as remote ischemic preconditioning (RIPC). The strongest protection occurs 24 hours after blood flow interruption to the limb and may be mediated by a humoral cascade known as kallikrein-kinin. RIPC may provide protection against heart attack and stroke.
Pharmacological Preconditioning And Sodium/hydrogen Exchange Inhibition To Optimise Preservation Of The Donor Pig Heart
Funder
National Health and Medical Research Council
Funding Amount
$242,545.00
Summary
Heart transplantation has become established as an extremely beneficial treatment for patients with end-stage heart failure, however its success is limited by the restricted availability of donor hearts. Many hearts that could be considered for heart transplantation cannot be used because of damage that can occur to potential donor hearts after the death of the donor. This damage is caused in part by deterioration in heart function after death and in part by the process of removal and cold stora ....Heart transplantation has become established as an extremely beneficial treatment for patients with end-stage heart failure, however its success is limited by the restricted availability of donor hearts. Many hearts that could be considered for heart transplantation cannot be used because of damage that can occur to potential donor hearts after the death of the donor. This damage is caused in part by deterioration in heart function after death and in part by the process of removal and cold storage that occur prior to transplantation of the heart. This study will examine two new methods of optimising the quality and preservation of the donor heart for transplantation. The treatments to be investigated in this study are aimed at preventing damage to the donor heart after death and during the process of transplantation. The studies will be conducted in a pig model of heart transplantation that we have developed in our laboratory. The treatments will be administered to the donor pig after induction of brain death and also to the recipient during transplantation of the heart. As the model closely mimics all aspects of human heart transplantation, any positive findings that stem from these studies will be directly applicable to human transplantation. Improved preservation of the donor heart will make the operation safer and will potentially increase the number of hearts that can be used for transplantation. As many donors provide multiple organs for transplantation eg kidneys, liver, lungs and pancreas, the treatments that we are investigating have the potential to improve the recovery of all these organs after transplantation.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