How Do P75 And Sortilin Facilitate TrkA-mediated Survival Signalling?
Funder
National Health and Medical Research Council
Funding Amount
$559,354.00
Summary
Neurotrophins are the classical growth factors that regulate neuronal survival and death throughout the nervous system in both the developing and adult animal. These factors signal through one of three receptors, but precisely how the receptors interact to propagate cell survival is unclear. The goal of this grant is to unravel the molecular basis underpinning this life and death signalling decision so that we can then devise ways to promote cell survival in neurodegenerative conditions
Mechanisms Of Ligand-Selective Signalling By Chemokine Receptors
Funder
National Health and Medical Research Council
Funding Amount
$749,428.00
Summary
Receptors are molecules located on the surfaces of cells. They control the response of one cell to chemical signals emitted by different cells. In this project we aim to characterise and understand the molecular details of how a receptor can respond differently to distinct chemical signals. The results of this study will help to guide future development of medicines to control white blood cell migration into tissues during inflammatory diseases such as heart disease, diabetes and arthritis.
Aldosterone Mediated Cardiac Pathophysiology:The Role Of Corticosteroid Receptors And 11 HSD Isoforms
Funder
National Health and Medical Research Council
Funding Amount
$481,500.00
Summary
Aldosterone a hormone that circulates in blood and is associated with cardiovascular disease. Recently, two clinical trials (RALES, EPHUSUS) demonstrate that if you stop this hormone from acting by giving drugs that inhibit it from binding to the receptor that mediates its response, there is an improvement in the health of heart failure patients. How aldosterone mediates its detrimental effects on heart is largely unknown. Glucocorticoids are another hormone that circulates in blood and can bind ....Aldosterone a hormone that circulates in blood and is associated with cardiovascular disease. Recently, two clinical trials (RALES, EPHUSUS) demonstrate that if you stop this hormone from acting by giving drugs that inhibit it from binding to the receptor that mediates its response, there is an improvement in the health of heart failure patients. How aldosterone mediates its detrimental effects on heart is largely unknown. Glucocorticoids are another hormone that circulates in blood and can bind to the same receptor as aldosterone. In contrast to aldosterone glucocorticoids appear to play a basic maintenance role in heart. Our central hypothesis is that in the healthy heart aldosterone has minimal effects , however, in the diseased heart aldosterone associated pathophysiology is a result of both an increase in the ability of aldosterone to signal to cells and disruption of glucocorticoid signalling. This grant proposal will address how aldosterone and glucocorticoids may directly signal within cardiac cells and how this signalling changes in the diseased heart. In addition, we investigate if enzymes that metabolize glucocortioids and thus render them non-functional play a role in cardiac disease, and if we can reverse the detrimental effects of aldosterone by artificially increasing the production of glucocorticoids in heart. By understanding the mechanisms by which aldosterone promotes cardiac disease, and the role of glucocorticoids and their metabolism in this process will lead to a better understanding of aldosterone induced pathology and thus lead to novel therapeutic targets.Read moreRead less
Last year an estimated 3.1 million people died of AIDS (source: UNAIDS, Dec 2002) equivalent to the number killed by tuberculosis and malaria combined. AIDS-related opportunistic infections (OIs) are the main cause of death for AIDS patients, especially in resource constrained countries where access to antiretroviral and antibiotic therapy is limited. Attempts to limit the epidemic have failed and new foci have emerged in Eastern Europe, Central Asia and, of particular relevance for us, South Ea ....Last year an estimated 3.1 million people died of AIDS (source: UNAIDS, Dec 2002) equivalent to the number killed by tuberculosis and malaria combined. AIDS-related opportunistic infections (OIs) are the main cause of death for AIDS patients, especially in resource constrained countries where access to antiretroviral and antibiotic therapy is limited. Attempts to limit the epidemic have failed and new foci have emerged in Eastern Europe, Central Asia and, of particular relevance for us, South East Asia, underlining the fact that safe and effective treatment for AIDS-related OIs will be a global health priority for the foreseeable future. People with healthy immune systems do not get OIs since the germs that cause such infections are efficiently ingested and subsequently destroyed by cells called macrophages. We have discovered that the virus that causes AIDS, HIV-1, interferes with the ability of macrophages to ingest opportunistic pathogens by the 2 most important mechanisms used for this purpose. We believe that this is the direct cause for the susceptibility of AIDS patients to many of the opportunistic pathogens that cause their OIs. The purpose of this grant will be to understand the biochemical basis underlying these 2 defects in macrophage function. This will help in the design of safe, adjunctive therapies aimed at improving macrophage function and reducing the risk of HIV-infected individuals developing AIDS-related OIs.Read moreRead less
Understanding Intrinsic And Acquired Resistance To Anti-FGFR Therapies
Funder
National Health and Medical Research Council
Funding Amount
$797,051.00
Summary
In vitro and in vivo preclinical data suggests that inhibition of FGFR in endometrial cancer patients may be a viable therapeutic approach. Data from other cancers suggests that despite remarkable initial responses to kinase inhibitors, cancer cells eventually develop resistance. This project aims to identify and characterize the mechanisms of resistance that emerge following FGFR inhibition in order to design combination therapies that may delay and/or prevent the emergence of resistance.
Mechanisms Of Pro-atherogenic Effects Of Androgens In Human Vascular Cells
Funder
National Health and Medical Research Council
Funding Amount
$211,320.00
Summary
Atherosclerosis is the most important cardiovascular disease and is now the leading cause of death in Western societies. A major clue to the causality of the disease is the striking gender gap in its prevalence and severity. The gender gap in atherosclerotic cardiovascular disease may be due to genetic, lifestyle or hormonal differences between males and females. Of these, hormonal differences are the most amenable to therapeutic intervention. Accordingly, there has been a lot of interest in the ....Atherosclerosis is the most important cardiovascular disease and is now the leading cause of death in Western societies. A major clue to the causality of the disease is the striking gender gap in its prevalence and severity. The gender gap in atherosclerotic cardiovascular disease may be due to genetic, lifestyle or hormonal differences between males and females. Of these, hormonal differences are the most amenable to therapeutic intervention. Accordingly, there has been a lot of interest in the potential protective effects of estrogens but few have studied the role of androgens with sophisticated approaches to androgen physiology and pharmacology. Clues from epidemiological and our recent studies suggest that androgenic influences on atherosclerosis may involve positive and negative effects on atherogenesis but the mechanisms are not understood. We now propose a comprehensive approach to studying androgenic effects on vascular biology both to enhance knowledge as well as potentially opening new therapeutic options in selective androgen receptor modulation.Read moreRead less
Novel Delta Receptor Expression In Opioid Tolerant/dependent Neurons
Funder
National Health and Medical Research Council
Funding Amount
$370,350.00
Summary
Opioids such as morphine and heroin act on specific molecular targets, or receptors, in the brain. Long term use of opioids produce changes in brain receptor systems that greatly diminish the effects of these drugs (tolerance), as well as producing an adverse withdrawal syndrome on cessation of use (physical dependence). The present proposal will identify the mechanisms of adaptations in cellular function in nerve cells critical for these changes. In particular, we have identified enhanced sensi ....Opioids such as morphine and heroin act on specific molecular targets, or receptors, in the brain. Long term use of opioids produce changes in brain receptor systems that greatly diminish the effects of these drugs (tolerance), as well as producing an adverse withdrawal syndrome on cessation of use (physical dependence). The present proposal will identify the mechanisms of adaptations in cellular function in nerve cells critical for these changes. In particular, we have identified enhanced sensitivity of receptor, the delta receptor, that is closely related to the opioid receptor but is not a target for heroin or morphine. We will identify the mechanisms of enhanced activity of this receptor after chronic use of morphine with a view to tergeting therapeutics to manage tolerance and physical dependence in opioid addicts and chronic pain patients.Read moreRead less
Dissecting The Role Of The IL-3 Receptor Alpha Subunit And Beta-catenin In Acute Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$583,312.00
Summary
Leukaemia is a devastating form of blood cancer affecting both young and old. We aim to understand the mechanisms of uncontrolled cell growth associated with acute myeloid leukaemia. We focus on the role of key growth regulators that are abnormally active in the critical leukaemia stem cells. Understanding the biological and molecular properties of these cells is of considerable importance for development of the next generation of leukaemia therapies.