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.
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
Targeting Necroptosis Signalling To Counter Stroke-induced Brain Injury
Funder
National Health and Medical Research Council
Funding Amount
$605,809.00
Summary
The origins of the brain injury that arises from stroke remain a matter of enormous interest. Our work suggests that a poorly understood form of cell death, termed necroptosis, contributes to injury to the brain following stroke. In addition to developing an advanced understanding of this process, we will use drugs developed at the Walter and Eliza Hall Institute to test whether blocking this process might be a plausible therapeutic strategy in stroke patients.
Discovery To Therapy Implementation In Acute Stroke
Funder
National Health and Medical Research Council
Funding Amount
$585,269.00
Summary
Advances in acute stroke therapies are occurring rapidly but challenges remain in their safe and effective delivery to stroke sufferers. This research focuses on testing a potentially superior ‘clot busting’ drug therapy for acute stroke and on identifying reasons why one of the most widely used current therapies carries a risk of significant harm due to bleeding into the brain. The work also investigates how to better implement the newest form of acute therapy, mechanical blood clot extraction.
Tenecteplase Versus Alteplase For Stroke Thrombolysis Evaluation (TASTE) Trial
Funder
National Health and Medical Research Council
Funding Amount
$4,180,030.00
Summary
Tenecteplase versus Alteplase for Stroke Thrombolysis Evaluation (TASTE) is an Australian-led international randomised trial designed to generate practice-changing evidence by translating the advanced imaging treatment selection approach used in our previous pilot studies. TASTE aims to confirm the superiority of the new-generation clot-dissolving agent, tenecteplase, over the standard agent, alteplase, in the broad group of stroke patients eligible for acute clot-dissolving treatment.
Acute Stroke: Imaging The Ischaemic Penumbra With Perfusion CT
Funder
National Health and Medical Research Council
Funding Amount
$243,000.00
Summary
The burden of stroke is large. Clot-dissolving medication (thrombolysis) may dramatically improve the outcome of many patients with severe stroke by unblocking the affected brain artery. However, very few patients receive this medication, as the current approval is restricted to treatment within 3 hours of stroke onset. The major aim of thrombolysis is to rescue brain tissue with reduced blood flow (the ischaemic penumbra) from becoming irreversibly damaged (infarcted). The penumbra progressivel ....The burden of stroke is large. Clot-dissolving medication (thrombolysis) may dramatically improve the outcome of many patients with severe stroke by unblocking the affected brain artery. However, very few patients receive this medication, as the current approval is restricted to treatment within 3 hours of stroke onset. The major aim of thrombolysis is to rescue brain tissue with reduced blood flow (the ischaemic penumbra) from becoming irreversibly damaged (infarcted). The penumbra progressively becomes infarcted over the next 48 hours if blood flow is not restored by the blood clot in the brain artery being dissolved. Penumbral brain tissue cannot be identified with clinical assessment or standard CT scanning. New generation CT scanners are capable of assessing brain blood flow. Perfusion CT imaging (CTP) is well tolerated and time-efficient, and can be integrated into the brain CT scanning process performed on all stroke patients. Preliminary evidence suggests that CTP can distinguish between tissue that represents the ischaemic penumbra, and tissue that is already permanently injured. This project aims to validate the use of CTP in imaging the ischaemic penumbra. This will be based on testing the accuracy of CTP tissue signatures of the penumbra in predicting clinical outcome and final stroke size. This is the only national collaborative study planned worldwide for this relatively new but increasingly accessible imaging technique. The ability to rapidly identify under-perfused but still viable brain with CTP would add new and exciting management options to the routine emergency assessment of stroke patients. The results of this unique study could have a significant impact on the management of acute stroke worldwide. If validated, it is anticipated that CTP would be widely used to improve patient selection for stroke thrombolysis, especially in safely extending the time window so that a greater number of patients can be treated with better outcomes.Read moreRead less