How Does Disruption Of Serinc1 Expression Affect Lymphocyte Function And The Development Of Autoimmunity?
Funder
National Health and Medical Research Council
Funding Amount
$681,555.00
Summary
Autoimmune diseases affect up to 8% of the population. We have recently discovered a novel gene mutation in mice that results in increased levels of anti-nuclear antibodies, a hallmark of various autoimmune diseases in humans. The mutated gene, Serinc1, has not been previously implicated in autoimmune disease, but it is important for synthesis of key molecules in immune cells. This research proposal aims to determine how disruption of Serinc1 contributes to the development of autoimmune disease.
Elucidating Mechanisms For The Biological Activities Of CD46.
Funder
National Health and Medical Research Council
Funding Amount
$228,000.00
Summary
The CD46 protein enables entry into cells of a number of different pathogens, including the measles virus, Neisseria meningitidis (the major cause of meningococcal disease), Neisseria gonorrhoea, Human Herpes Virus 6, and group A streptococcus. In addition, by binding to a key blood component that is often attached to foreign pathogens, CD46 can facilitate binding and entry of other pathogens. As well as facilitating entry of the pathogen, it has recently become apparent that CD46 binding trigge ....The CD46 protein enables entry into cells of a number of different pathogens, including the measles virus, Neisseria meningitidis (the major cause of meningococcal disease), Neisseria gonorrhoea, Human Herpes Virus 6, and group A streptococcus. In addition, by binding to a key blood component that is often attached to foreign pathogens, CD46 can facilitate binding and entry of other pathogens. As well as facilitating entry of the pathogen, it has recently become apparent that CD46 binding triggers a wide range of responses from the human host. Some of these responses are likely to further facilitate survival and proliferation of the pathogen, but others are more likely to facilitate host defence. For examples, signals triggered by binding to CD46 can both abrogate some aspects of the immune response (and it is though that this immunosuppression contributes to the secondary infections that cause the death of nearly one million children each year) and facilitate other aspects of the immune response. By understanding the mechanisms by which CD46 triggers these complex responses, we firstly be able to dissect how important each of these processes are to the overall pathogenecity of the virus or bacteria. Furthmore, this understanding will allow us to design better vaccines and drugs to combat these diseases.Read moreRead less
Ischaemia-induced Sarcolemmal Changes And Their Role In Ins(1,4,5)P3 Generation And Arrhythmogenesis
Funder
National Health and Medical Research Council
Funding Amount
$468,750.00
Summary
Studies in our laboratory at the Baker Heart Research Institute over the last several years have identified a novel mechanism causing the development of arrhythmias, a primary cause of sudden cardiac death in heart failure as well as during an acute heart attack caused by acutely reduced blood flow. The reduced blood flow leads to lowered oxygen and nutrients and thus the beating heart cells have insufficient energy to properly maintain function. Under these stressed conditions, cardiac myocytes ....Studies in our laboratory at the Baker Heart Research Institute over the last several years have identified a novel mechanism causing the development of arrhythmias, a primary cause of sudden cardiac death in heart failure as well as during an acute heart attack caused by acutely reduced blood flow. The reduced blood flow leads to lowered oxygen and nutrients and thus the beating heart cells have insufficient energy to properly maintain function. Under these stressed conditions, cardiac myocytes produce large amounts of a small molecule called IP3, which interferes with the normal electrical balance of the cells. Blocking IP3 generation prevents arrhythmias under these acutely ischaemic conditions. In more recent studies, we have identified many of the enzymes responsible for generation of IP3 in heart cells and have defined the properties of the regions of the cell responsible for this response. We now want to establish exactly how a period of ischaemia alters the localization or functioning of the enzymes that are responsible for this pathological change that leads to fatal arrhythmias.Read moreRead less
The Role Of Plasma Membrane Microdomains In Regulating Ras-dependent Raf Activation
Funder
National Health and Medical Research Council
Funding Amount
$216,100.00
Summary
In human cancers one or more of the signaling pathways leading from growth factor receptors at the cell surface to the nucleus where cell division is initiated are subverted. For example, a protein called Ras, that regulates a series of major signaling pathways, is mutated in 25% of all human tumours. This leaves Ras and the signaling pathways permanently switched on causing uncontrolled cell proliferation. Our previous work has demonstrated that Ras must be attached to the inner surface of the ....In human cancers one or more of the signaling pathways leading from growth factor receptors at the cell surface to the nucleus where cell division is initiated are subverted. For example, a protein called Ras, that regulates a series of major signaling pathways, is mutated in 25% of all human tumours. This leaves Ras and the signaling pathways permanently switched on causing uncontrolled cell proliferation. Our previous work has demonstrated that Ras must be attached to the inner surface of the cell membrane in order to function properly. This project now seeks to understand exactly how Ras attaches to and interacts with specific sites in the plasma membrane. Its is becoming clear that different isoforms of Ras, called H-, N- and K-ras have different functions in the cell which may in turn result from their different sites of attachment to the cell membrane. This is important because by understanding the precise micro-environment in which the different Ras proteins operate and how they activate subsequent proteins in their signaling networks we will be in a good position to design drugs that selectively compromise the function of each specific Ras isoform. A highly relevant example is provided by K-ras which is mutated in 90% of all pancreatic cancers and 50% of all colon cancers. Clearly the clinical impact of a drug that could selectively neutralise K-Ras function in these tumours is potentially enormous.Read moreRead less
The activation of T lymphocytes is essential part of our immune system to fend off harmful intruders. Our research aims to understand the process of T cell activation, in particular, the contribution of fats. We found that fats create a highly ordered patch at the T cell activation site. We want to understand how lipids and proteins work together to activate T cells, how this ordered regions function in T cell activation and whether dietary lipids alter these patches and thus T cell activation.
Regulation Of Secretion Of The Fungal Virulence Determinant, Phospholipase B
Funder
National Health and Medical Research Council
Funding Amount
$487,500.00
Summary
Serious systemic infections due to fungi have increased dramatically in the past few years, especially in people with poorly functioning immune systems. Treatment of these conditions is problematic because the few drugs which are available are not highly effective, and-or cause significant side-effects. Little is understood of how fungi cause disease, and this problem must be addressed if these infections are to be contained. We have discovered that the enzyme, phospholipase B (PLB), is secreted ....Serious systemic infections due to fungi have increased dramatically in the past few years, especially in people with poorly functioning immune systems. Treatment of these conditions is problematic because the few drugs which are available are not highly effective, and-or cause significant side-effects. Little is understood of how fungi cause disease, and this problem must be addressed if these infections are to be contained. We have discovered that the enzyme, phospholipase B (PLB), is secreted by the disease-causing fungus, Cryptococcus neoformans, and that it is important in enabling the fungus to invade the host's cells and spread around the body from the lungs to the brain, where it can cause meningoencephalitis. PLB is also produced by other disease-causing fungi. The mechanism of PLB secretion is completely unknown. In this project we aim to determine the pathways involved in PLB secretion with the intention of exploiting steps unique to pathogenic fungi, for the future design of new anti-fungal drugs.Read moreRead less
The Role Of Seipin In Lipid Metabolism And Adipogenesis
Funder
National Health and Medical Research Council
Funding Amount
$397,749.00
Summary
The prevalence of obesity and its related disorders has reached an alarming level in Australia and other developed countries. Obesity is characterized by accumulation of fully-differentiated adipocytes loaded with lipid droplets (LDs). Therefore, understanding the cellular dynamics of LDs and the molecular mechanisms of adipogenesis (adipocyte differentiation) is of crucial importance in our battle against obesity. Our proposed study will help undertand the mechnisams of obesity.
Elucidating Metabolic Dysregulation In Alzheimer’s Disease: Profiling The Peripheral Immune Cell Lipidome To Unravel Pathological Mechanisms.
Funder
National Health and Medical Research Council
Funding Amount
$645,205.00
Summary
Both the immune system and lipid metabolism have been identified to be important in Alzheimer’s disease (AD). With the failures of all clinical trials attempting to treat AD, we seek to determine a way to both better diagnose individuals with AD and to identify people at increased risk. This project uses a novel profiling technique to characterise the lipid composition of immune cells to diagnose, predict risk, monitor the disease and to identify potential disease modifying therapeutic targets.