Investigating Hippo Signalling As A Novel Cause Of Muscle Disease, And As A Target For New Interventions To Combat Frailty
Funder
National Health and Medical Research Council
Funding Amount
$460,509.00
Summary
We will explore the role of the Hippo signaling pathway in muscle development, repair and remodelling. We propose that this little-known pathway which affects organ development, is key for maintaining healthy muscles, and is affected in muscle wasting. Using gene therapy tools to alter this pathway in models of disease, we intend to clarify the role of Hippo signaling in muscle, and establish whether the pathway can be manipulated to treat physical frailty caused by muscle wasting.
Pathogenesis Of Antiretroviral Induced Sub-cutaneous Fat Wasting
Funder
National Health and Medical Research Council
Funding Amount
$331,650.00
Summary
The use of potent antiretroviral therapy has resulted in great clinical and survival benefit in patients with HIV infection and has in most cases, outweighed the risk of short term side effects. However, not that survival of patients with AIDS has considerably improved the long-term complications of chronic therapy have become a critical issue. Lipodystrophy syndrome(s) is the name given to a set of changes to blood lipids, glucose levels and body habitus and typically occurs in those successful ....The use of potent antiretroviral therapy has resulted in great clinical and survival benefit in patients with HIV infection and has in most cases, outweighed the risk of short term side effects. However, not that survival of patients with AIDS has considerably improved the long-term complications of chronic therapy have become a critical issue. Lipodystrophy syndrome(s) is the name given to a set of changes to blood lipids, glucose levels and body habitus and typically occurs in those successfully treated with anti-HIV therapy. The facial and body habitus changes are common, progressive and are frequently disfiguring. Aside from the psychological and social effects of such changes, many patiens are not able to retain their anonymity as HIV infected individuals. In addition, changes to blood lipids may lead to atherosclerosis. Already there have been several case reports of premature coronary disease in young HIV infected patients. It is increasingly difficult for patients to remain strictly adherent to chronic therapy because of all these concerns. There is an urgent need to understand the exact biological cause(s) of lipodystrophy syndrome(s) in HIV infected patients in order to help identify which of our currently available antiretroviral therapies will offer the long term clinical and survival benefit of strong viral suppression without increasing risk of vascular disease. Based on results of our previous studies on lipodystrophy syndrome, we have proposed that lipodystrophy may be the result of antiviral drugs depleting the DNA content of mitochondria within fat cells. We propose to examine sequential fat biopsy specimens from HIV infected volunteers to determine whether antiretroviral therapy has had adverse effects on mitochondrial DNA content and-or function.Read moreRead less
Activin Type II Receptor Antagonists: Mechanism Of Action And Biological Applications
Funder
National Health and Medical Research Council
Funding Amount
$507,270.00
Summary
Activin is a member of the TGF- family of growth and differentiation factors. Over-expression in mice leads to muscle and liver wasting, scarring during wound healing, disturbances to the reproductive system and various endocrine disorders. Activin's biological activity is promoted by its binding in series to two receptors termed Type I and II. Previous studies by this investigator have shown that selective modification of activin's protein structure can result in activin forms (in this instance ....Activin is a member of the TGF- family of growth and differentiation factors. Over-expression in mice leads to muscle and liver wasting, scarring during wound healing, disturbances to the reproductive system and various endocrine disorders. Activin's biological activity is promoted by its binding in series to two receptors termed Type I and II. Previous studies by this investigator have shown that selective modification of activin's protein structure can result in activin forms (in this instance called activin-M108A) which bind to Type II receptors but fail to promote binding to the Type I receptor. This has led to the hypothesis that activin-M108A may compete for native activin binding to Type II receptors and thus prevent activin's recruitment of the Type I receptor with the consequence that activin's biological activity is inhibited. It is proposed to test this hypothesis by producing sufficient amounts of activin-M108A and testing its inhibitory effects in several mouse models of liver damage, muscular degeneration and ovarian and testicular disease. If activin-M108A, or related modified forms of activin, decrease the morbidity and mortality associated with these murine diseases, then we envisage that these activin type II receptor antagonists will also be beneficial for the treatment of related human conditions.Read moreRead less
Urine Proteomics As A New Diagnostic Approach For Cardiovascular Risk And As A Discovery Tool For Novel Pathomechanisms In Atherosclerotic Disease
Funder
National Health and Medical Research Council
Funding Amount
$69,500.00
Summary
Atherosclerosis (hardening of blood vessels) followed by blockage is the leading cause of death due to heart attacks and strokes. Up until now there has been no simple tests to predict this reliably.The outcome of this project will give us a better understanding of atherosclerosis and provide a simple non-invasive urine test to detect atherosclerosis which would lend clinicians the opportunity to intervene early.
Evaluation Of Optimal Pharmacologic Haemodynamic Support Strategies In Patients Presenting With Shock
Funder
National Health and Medical Research Council
Funding Amount
$132,743.00
Summary
Shock is one of the most challenging clinical management scenarios experienced by clinicians. It is a syndrome characterised by an imbalance of oxygen delivery and demand particularly in vital organs. Despite the advances in current treatment strategies for patients with shock, there is still significant morbidity and mortality associated with this syndrome. It is the goal of my PhD to develop improved treatment pathways for patients with shock in order to improve their clinical outcomes.
Centre Of Excellence For Clinical Research Training In Translational Cardiology
Funder
National Health and Medical Research Council
Funding Amount
$2,622,253.00
Summary
We aim to convert novel scientific findings to better treating patients with end-stage heart disease. A secondary aim is to train clinicians with a better understanding of sophisticated scientific approaches so they can better transfer this knowledge to health practices and policies. We will study new ways of identifying patients who are likely to suffer from heart attacks as well as those with heart problems who appear to function well but in fact have poor health and life outlook.
Optimizing Evidence Translation In The High-risk Time-critical Environment Of The Emergency Management For Suspected Cardiac Chest Pain (RAPIDx)
Funder
National Health and Medical Research Council
Funding Amount
$1,230,191.00
Summary
Few clinical processes are purposefully redesigned to optimally incorporate new diagnostic test into routine practice. Using artificial intelligence to enhance the interpretation of newly identified troponin elevation with high sensitivity troponin assays, we will implement a myocardial injury registry in practice. It will also form a platform to explore the clinical impact of artificial intelligence, through a cluster randomized trial evaluating decision-support on 12-month outcomes.
The Role Of New Generation Multidetector Row CT For Identification And Management Of Vulnerable Plaque At Risk Of Acute Coronary Syndrome : A Prospective Observational And Interventional Study
Funder
National Health and Medical Research Council
Funding Amount
$189,326.00
Summary
Heart attack remains one of the major cause of death. This is usually due to rupture of a plaque (due to cholesterol buildup) in the major heart arteries. Studies using invasive ultrasound have identified some features of plaque that are at high risk of rupture. These plaques are referred to as "vulnerable plaque". Recent developments in the computed tomography (CT) technology which is a non-invasive technique has enabled us to also identify these features. However thus far, no prospective large
Cachexia is a major side effect of cancer, resulting in significant muscle wasting, fat loss and organ failure. Up to 80% of cancer patients suffer and 25% succumb to this condition. This significantly affects the treatment regimens of cancer patients and affects their quality of life. We have developed monoclonal antibodies that block and reverse cachexia in preclinical mouse cancer models. Our aims are to humanise the antibody and manufacture it for the first clinical trial in humans.
Demystifying The Burden Of Intensive Care Survivorship - Understanding Muscle Wasting And Falls
Funder
National Health and Medical Research Council
Funding Amount
$314,644.00
Summary
For individuals who survive an intensive care admission, there is no prevention or cure for the development of intensive care acquired weakness. This project aims to examine the impact of muscle loss and weakness on balance, falls and the ability to walk. These outcomes are important to patients as it directly impacts on the ability to undertake day-to-day activities, their confidence and return to work. Results will be used to inform clinical practice and improvement in patient care.