Functional Suicide Of Selected Dendritic Cells By Cytochrome C: An In Vivo Model Lacking Cross-presentation
Funder
National Health and Medical Research Council
Funding Amount
$597,476.00
Summary
Certain white blood cells (dendritic cells) activate the immune system, especially its T cells. Infection of such cells elicits killer T cell responses. However not all infections infect dendritic cells. In such cases, the infectious material is eaten by dendritic cells and moved to certain areas within the cell. This process is called cross-presentation and how important it is during various diseases remains moot. We now have a model of testing this by eliminating these cross-presenting cells.
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.
Restoration Of The Nigrostriatal Pathway In The Parkinsonian Brain
Funder
National Health and Medical Research Council
Funding Amount
$299,431.00
Summary
Many obstacles exist for cell transplantation in Parkinson's disease; namely poor restoration of the host brain circuitry due to incorrect graft placement. This results in incomplete motor function and unwanted side effects. Through iterative studies we endeavor to restore this circuitry by placing grafts in the appropriate location and promoting their survival and growth-integrations. This will require: optimizing the donor tissue and exposure of the graft to growth stimulating factors.
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
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
Salt And Cardiovascular Disease: Does Acute Salt-Sensitivity Convey Greater Cardiovascular Risk?
Funder
National Health and Medical Research Council
Funding Amount
$597,578.00
Summary
Salt intake of Australian adults is 10X more than required. Further, salt intake in very young children is alarmingly high secondary to high consumption of salty snacks and processed food. High dietary salt intake has been associated with increased cardiovascular disease and death. We will examine the cardiovascular risks for adults and children on a high salt diet and examine whether switching to a low salt diet ameliorates the high blood pressure and heart disease caused by high salt diets
Wnt Signaling In Dopaminergic Neuronal Connectivity
Funder
National Health and Medical Research Council
Funding Amount
$564,721.00
Summary
A major obstacle in repairing the injured or diseased brain is inducing axons (nerve cell processes) to make the appropriate connections. This is especially true following cell replacement therapy (CRT) in Parkinson's disease (PD). We will examine the processes inducing axons in the dopamine pathways to grow. We hypothesize that Wnt signaling plays and important role and that therapeutic introduction of Wnt is required to repair the dopamine pathways following CRT in PD.
STudy Of Risk Assessment To Reduce Complications In Patients Following Noncardiac SurgerY (STRATIFY)
Funder
National Health and Medical Research Council
Funding Amount
$436,000.00
Summary
Cardiac problems account for many complications in patients undergoing major non-cardiac surgery, and even apparently minor cardiac damage is a marker of high risk for subsequent adverse events. Unfortunately, while money and effort is expended on identifying patients at risk, the appropriate response to this risk is quite unclear. The performance of bypass surgery or balloon angioplasty in order to treat the underlying coronary disease of at-risk patients is used in other situations, and reduce ....Cardiac problems account for many complications in patients undergoing major non-cardiac surgery, and even apparently minor cardiac damage is a marker of high risk for subsequent adverse events. Unfortunately, while money and effort is expended on identifying patients at risk, the appropriate response to this risk is quite unclear. The performance of bypass surgery or balloon angioplasty in order to treat the underlying coronary disease of at-risk patients is used in other situations, and reduces longterm risk. However, in many patients undergoing major noncardiac surgery, this approach may be inappropriately aggressive, as these patients are often elderly, have other diseases that make heart operations more difficult and risky than usual, and in any case may have a reduced life expectancy from the disease necessitating the operation. As the most critical issue is to ensure that patients undergo their surgery uneventfully, an alternative is the use of intensive medical therapy to protect the heart. This multicentre study, based at Brisbane hospitals that perform large numbers of major operations, will follow up patients for complications, and outcome (including quality of life) will be assessed six months after the operation. We will address two important questions about the efficacy and cost of risk reduction strategies. First, in patients at higher levels of risk and with a positive stress test, could a combination of medical therapy designed to protect the heart be as effective as current approaches, which include the performance of bypass surgery or coronary balloon angioplasty? Second, in patients identified as being at some risk - but low risk - are drugs sufficiently effective to avoid the need for further testing to quantify risk? As the population continues to age, the numbers of at risk patients undergoing major surgery will increase, and answers to these questions will provide important information to guide their management.Read moreRead less
Characterisation Of Human Embryonic Stem Cell Differentiation To Haematopoietic Progenitors And Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$638,856.00
Summary
Blood stem cells, which are found in the bone marrow, are currently used for treating human blood disorders including leukemia and lymphoma. However, for the majority of bone marrow transplant candidates, suitable donors cannot be found. Using embryonic stem cells, this project aims to define the conditions required to generate blood stem cells in the laboratory. The aim of the work is to provide a new source of blood stem cells that could be used in place of donor derived bone marrow.
Enhancing Erythropoietin Therapy In Ischaemia-reperfusion Injury Of Heart And Kidney
Funder
National Health and Medical Research Council
Funding Amount
$361,021.00
Summary
Heart attacks and kidney disease from a lack of blood flow are common causes of morbidity and have poor treatment options. Erythropoietin (epo) is a useful new treatment, but there remain some caveats to its use in humans: eg. it may cause excessive scarring during repair. Use of epo with an anti-inflammatory drug may decrease scarring and provide benefit to long-term health. We plan to carefully define the biomolecular pathways of injury and repair, to better plan this therapy for human use.