Unraveling Fibrosis By Pharmacological Targeting Of The G Protein-coupled Receptor, RXFP1
Funder
National Health and Medical Research Council
Funding Amount
$798,618.00
Summary
Peptides, with their high specificity and low toxicity profiles, are highly attractive alternatives to small molecule drugs. H2 relaxin, a peptide hormone, has a strong potential for treating fibrosis. However, the large size of H2 relaxin makes it difficult and expensive to manufacture. Once administered to patients, it is also quickly degraded. We have developed a small anti-fibrotic relaxin peptide, and propose to understand its mechanism of action and improve its therapeutic indices.
This research proposal will identify changes in liver-secreted proteins during the development of fatty liver, and in the transition from fatty liver to the more advanced form of liver disease, non-alcoholic steatohepatitis (NASH). Understanding the differences in protein secretion between NASH patients and patients with normal/fatty liver will provide the opportunity to identify disease biomarkers that could be determined from a blood sample. This will provide a major shift in clinical care.
Improving The Long-term Outcomes Of The Australian And New Zealand Fontan Population
Funder
National Health and Medical Research Council
Funding Amount
$89,836.00
Summary
The Fontan procedure is the last of a series of operations offered to children born with hearts with a single pumping chamber. Without this procedure these children would die, however, with this procedure their long-term expectations are still uncertain. This study will investigate the long-term outcomes of the Australian and New Zealand Fontan population and how these outcomes can be improved.
Attenuating Severe Infections In Chronic Inflammatory Diseases Through Modulation Of Transforming Growth Factor-β Activity
Funder
National Health and Medical Research Council
Funding Amount
$611,793.00
Summary
Asthma and chronic obstructive pulmonary disease (COPD) are characterised by enhanced TGF? expression, which is accompanied by susceptibility to recurrent viral and bacterial infections. Such infections exacerbate lung inflammation in these patients, generally requiring emergency department treatment. This project proposes to clarify the therapeutic potential of TGF? inhibitors to reduce the impact of viral infections in patients with COPD and asthma.
Optimising Heart Disease Prevention And Management
Funder
National Health and Medical Research Council
Funding Amount
$4,647,175.00
Summary
As we become older and risk factors such as obesity become more common, our biggest contributor to death and disability, cardiovascular disease (including heart disease), will continue to exert an enormous burden on our health care system and society. We will extend our ground-breaking research on multidisciplinary teams to create new and innovative health care programs to optimise the prevention and management of new heart disease and chronic forms of heart disease.
Improving The Prevention, Treatment And Management Of Cardiovascular & Chronic Disease In The Community
Funder
National Health and Medical Research Council
Funding Amount
$774,540.00
Summary
The identification, prevention and management of cardiovascular and chronic disease risk factors and understanding impact on clinical outcomes is fundamental to improving health and well-being. The program of work encapsulated in this application utilises modern epidemiological research methods involving large scale clinical trials, registries and epidemiological modelling to advance our understanding and provide new directions for cardiovascular disease prevention and management.
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
Novel Vasoactive Pathways In Liver Disease; Experimental And Clinical Studies
Funder
National Health and Medical Research Council
Funding Amount
$535,333.00
Summary
Cirrhosis of the liver due to chronic hepatitis and other common liver diseases is now a major cause of illness and death in Australia. This project will examine how a hormone system called the renin angiotensin system contributes to the development of liver damage in these diseases. We will study whether drugs targeting this system can be used to reduce liver scarring and prevent the development of cirrhosis and its complications.
Revolutionising The Diagnosis And Monitoring Of CF Lung Disease
Funder
National Health and Medical Research Council
Funding Amount
$818,391.00
Summary
Cystic fibrosis (CF) lung disease starts early in childhood and relentlessly progresses, with early death a common outcome. There is currently no method capable of detecting very early disease onset nor directly assessing the effectiveness of putative treatments. This project will apply our globally unique X-ray imaging tools, which are capable of imaging lung function at any point across the entire lung, for the very early detection of CF and assessment of clinically applicable treatments.
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