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
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.
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.
GABA Excitotoxicity, Neuroprotection And The Perinatal Brain
Funder
National Health and Medical Research Council
Funding Amount
$547,970.00
Summary
Approximately 3.5% of babies die each year from brain damage due to perinatal asphyxia, a shortage of oxygen to the developing brain. Babies that survive face lifelong neurological disabilities, placing enormous burden on health, social and economic resources. Current treatments are inadequate. We will examine what occurs when there is a shortage of oxygen to the developing brain and investigate pathways to hypoxic brain injury that offer opportunities for therapeutic intervention.
Early Identification Of Infants Who Will Benefit From Neural Rescue Treatment
Funder
National Health and Medical Research Council
Funding Amount
$206,320.00
Summary
Lack of oxygen supply before, during or immediately after birth can lead to severe disability or death. This occurs in about 1 in every 500 births and is one of the most important but unsolved problems in pediatrics. The costs (financial and other) to both the individuals involved, and the community in general, is very high. However the outlook for those affected by this condition is improving. Recent research has focused on the development of neural rescue therapies, which may decrease the exte ....Lack of oxygen supply before, during or immediately after birth can lead to severe disability or death. This occurs in about 1 in every 500 births and is one of the most important but unsolved problems in pediatrics. The costs (financial and other) to both the individuals involved, and the community in general, is very high. However the outlook for those affected by this condition is improving. Recent research has focused on the development of neural rescue therapies, which may decrease the extent of disabilities suffered by these children. The same treatments may also be helpful in children following near drowning and head trauma. Neural rescue therapies must be applied less than 24 hours following the event which has caused the reduction in oxygen supply. Thus, before these treatments can be tested, it is necessary to find a way to quickly tell which babies may benefit from the treatments. This study will trial a new method which is inexpensive and can be used without moving the baby away from its incubator. This technique involves a new application of an established technology to detect the redistribution of water within the brain one of the earliest signs of impending brain cell death. The research team consists of medical personnel from the intensive care nurseries of both the Royal Women's Hospital and the Mater Mother s Hospital, as well as scientific staff experienced in the use of this technology. If this technique is effective, it will enable babies to receive maximum benefit from new treatments and reduce long-term difficulties suffered by these children and their families.Read moreRead less
Novel Approaches To Assessing Cerebral Circulation And Oxygenation In Preterm Human Infants.
Funder
National Health and Medical Research Council
Funding Amount
$489,145.00
Summary
In the first few days after birth, some premature babies develop low blood pressure. It is thought that this meant that the amount of blood and oxygen going to the brain would also fall. If blood pressure became very low, this could injure the brain. Drugs are used to prevent low blood pressure, but their effect on blood flow and oxygen in the brain is uncertain. This study aims to develop simple cotside monitoring procedures that allow neonatologists to monitor oxygen supply and blood flow in t ....In the first few days after birth, some premature babies develop low blood pressure. It is thought that this meant that the amount of blood and oxygen going to the brain would also fall. If blood pressure became very low, this could injure the brain. Drugs are used to prevent low blood pressure, but their effect on blood flow and oxygen in the brain is uncertain. This study aims to develop simple cotside monitoring procedures that allow neonatologists to monitor oxygen supply and blood flow in the brain in tiny babies who weigh less than 1000gm, and what happens within the brain when drugs are given to raise blood pressure. We will employ a new instrument that generates low intensity near infrared light which passes safely into the brain and is absorbed according to the amount of oxygen present in very small blood vessels. As the methodology is new, we intend to first validate the measurement in immature lambs. The instrument will then be applied in studies of babies undergoing intensive care and at risk for low pressure and brain injury, as many as 5000 babies each year in Australia.Read moreRead less
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