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
Identifying The Site/s Of Modification On The Human L-type Ca2+ Channel Protein Isoforms During Oxidative Stress With Reference To Development Of A Therapeutic Target
Funder
National Health and Medical Research Council
Funding Amount
$360,369.00
Summary
A rise in calcium and free radicals in the heart are associated with the development of heart disease. We have good evidence that a protein in the heart muscle known as the L-type calcium channel mediates changes in calcium in response to free radicals. This proposal will identify how the channel function is altered by free radicals so that a therapeutic target can be designed to prevent altered channel function and development of heart disease during increases in free radicals.
Targeting PI3K-regulated MicroRNAs To Treat Heart Failure
Funder
National Health and Medical Research Council
Funding Amount
$532,593.00
Summary
Current therapeutics largely delay heart failure progression rather than regressing it. New therapeutic strategies with the capability of improving function of the failing heart are thus greatly needed. The primary goal of this study is to determine whether novel regulatory genes can enhance cardiac function in a setting of heart failure. Ultimately, technologies that target these genes may lead to innovative pharmacotherapies in the clinical management of heart failure.
New antiparasitics to protect Australian livestock. There is an urgent need for new antiparasitics to treat multi-drug resistant livestock infections. This project aims to explore the bacteria and fungi present in the microbiomes of heavily infected sheep faeces and pastures, challenging them with environmental cues, including those from associated parasites, to stimulate production of defensive chemicals hidden deep within their genomes. Enabled by an integrated pipeline of high throughput anal ....New antiparasitics to protect Australian livestock. There is an urgent need for new antiparasitics to treat multi-drug resistant livestock infections. This project aims to explore the bacteria and fungi present in the microbiomes of heavily infected sheep faeces and pastures, challenging them with environmental cues, including those from associated parasites, to stimulate production of defensive chemicals hidden deep within their genomes. Enabled by an integrated pipeline of high throughput analytical cultivation, molecular networking, and chemical and biological analyses, expected outcomes include an enhanced ability to explore and exploit valuable chemistry hidden within microbial genomes, leading to the discovery of new classes of natural antiparasitic to safeguard livestock.
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Urotensin-II In Human Heart: Investigation Of Mechanisms Involved In Cardiac Function
Funder
National Health and Medical Research Council
Funding Amount
$255,990.00
Summary
The normal function of the body is maintained by naturally occurring compounds. Some for example affect the heart, fine tuning it to make it beat faster or slower, or beat with greater or less force when required in different situations in health and disease. We were the first to show just recently that a small protein which occurs naturally in the body, called urotensin-II can affect the way the heart beats. We showed that extremely tiny amounts increase the force of the heart beat. Our finding ....The normal function of the body is maintained by naturally occurring compounds. Some for example affect the heart, fine tuning it to make it beat faster or slower, or beat with greater or less force when required in different situations in health and disease. We were the first to show just recently that a small protein which occurs naturally in the body, called urotensin-II can affect the way the heart beats. We showed that extremely tiny amounts increase the force of the heart beat. Our findings indicate that urotensin-II is the most potent heart stimulator identified to date. In patients with heart failure, short term stimulation of heart contraction is beneficial, supplying the heart and other organs with vital oxygen and nutrients. However, in the long term excessive stimulation causes worsening of the patients condition. Very little is currently known about the way in which urotensin-II alters heart function. The goal of our study is to understand the mechanism involved in urotensin-II mediated effects on the heart. This will involve identifying the location of urotensin-II and its receptors in the heart, and determining what signalling changes occur after the interaction of urotensin-II with its receptors. Urotensin-II must first be cleaved from a larger drug. We will determine where in the heart this cleavage occurs and whether the process is crucial to the ability of urotensin-II to stimulate contraction of the heart. Since stimulators of heart contraction are detrimental to patients with heart failure in the long term, we will determine whether these patients have more urotensin-II in their blood than patients who do not have heart failure. If the levels of urotensin-II are higher in heart failure patients, it may indicate a need to interfere with the interaction of urotensin-II with its receptors.Read moreRead less
Australian Resuscitation Outcomes Consortium [AUS-ROC] CRE
Funder
National Health and Medical Research Council
Funding Amount
$2,668,571.00
Summary
The Australian Resuscitation Outcomes Consortium (Aus-ROC) will be modelled on the highly successful North American Resuscitation Outcomes Consortium. The mission of Aus-ROC will be to conduct clinical trials and observational studies into the emergency management of out-of-hospital cardiopulmonary arrest. Building on our existing collaborative partnerships, our goal is to improve patient outcomes and build the research capacity in prehospital emergency care.
Insecticide targets in the nervous system: Discovery and design for sustainable insect pest control. Insect pests impose massive costs in food production, in human health and in the wellbeing of our companion animals. Chemical insecticides remain a major weapon in the control of these pests, but the use of insecticides has some downsides. The way in which insecticides kill insects is poorly understood and insecticide usage has negative impacts in the environment – the persistence of chemical r ....Insecticide targets in the nervous system: Discovery and design for sustainable insect pest control. Insect pests impose massive costs in food production, in human health and in the wellbeing of our companion animals. Chemical insecticides remain a major weapon in the control of these pests, but the use of insecticides has some downsides. The way in which insecticides kill insects is poorly understood and insecticide usage has negative impacts in the environment – the persistence of chemical residues and the killing of beneficial insects along with the pests. Further, insects become resistant to insecticides, so pest control is lost. This proposed research seeks to identify the ‘achilles heal’ in insect pests and to target them with new generation insecticides to gain safe, effective and sustainable control.Read moreRead less
Development of Novel Pesticidal Agents. We have discovered a family of naturally occurring plant proteins called the cyclotides that have potent insecticidal activity against Helicoverpa species, one of the major pests on cotton and corn in Australia and world wide. Preliminary evidence has shown that they also have activity against major pests to livestock in Australia, including sheep blowflies. To develop these proteins as potential pesticidal agents it is necessary to understand the struct ....Development of Novel Pesticidal Agents. We have discovered a family of naturally occurring plant proteins called the cyclotides that have potent insecticidal activity against Helicoverpa species, one of the major pests on cotton and corn in Australia and world wide. Preliminary evidence has shown that they also have activity against major pests to livestock in Australia, including sheep blowflies. To develop these proteins as potential pesticidal agents it is necessary to understand the structural basis for their activity. We will do this by chemically synthesising peptides with selected residues mutated to determine their effects on activity.Read moreRead less
Rethinking and revitalising herbicides to counter resistance. Weeds and increasingly herbicide resistant weeds are the major yield penalty for agriculture. This project aims to develop innovative ways to overcome resistance. This project expects to (i) make herbicides work more efficiently, (ii) reveal a new mode of action for an under-used herbicide and (iii) assign breakdown pathways to herbicides. Expected outcomes of this project are to (i) to find rare, but truly synergistic herbicide combi ....Rethinking and revitalising herbicides to counter resistance. Weeds and increasingly herbicide resistant weeds are the major yield penalty for agriculture. This project aims to develop innovative ways to overcome resistance. This project expects to (i) make herbicides work more efficiently, (ii) reveal a new mode of action for an under-used herbicide and (iii) assign breakdown pathways to herbicides. Expected outcomes of this project are to (i) to find rare, but truly synergistic herbicide combinations; (ii) reveal a herbicide against which weeds outside of Japan have not evolved resistance to; and (iii) establish how best to make breakdown blockers. A benefit of using existing herbicides is the approaches are close to market, so with partner Nexgen Plants, its outcomes can be commercialised.Read moreRead less
Investigating insect neuronal plasticity under genetic and chemical stress. This project aims to study receptors that translate chemical signals into electrical signals in animal brains. These receptors are targeted by insecticides used to control the major pests that afflict agriculture and domestic pets. The project aims to establish the functions of nicotinic acetylcholine receptors in several behaviours and in insecticide responsiveness in the model insect, Drosophila melanogaster, using mut ....Investigating insect neuronal plasticity under genetic and chemical stress. This project aims to study receptors that translate chemical signals into electrical signals in animal brains. These receptors are targeted by insecticides used to control the major pests that afflict agriculture and domestic pets. The project aims to establish the functions of nicotinic acetylcholine receptors in several behaviours and in insecticide responsiveness in the model insect, Drosophila melanogaster, using mutations that knock out the function of receptor subunits. Prior research has pointed to plasticity in the expression and transport of these receptors in response to genetic and environmental change. This project aims to identify the underlying mechanisms that provide the insect with resilience, to provide better options for pest control.Read moreRead less