The Role Of Endothelial Lipase In High Density Lipoprotein Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$130,550.00
Summary
Atherosclerosis is a major cause of death and disability in Australia. A high level of blood cholesterol increases the risk of developing atherosclerosis. This increase in risk is caused by the cholesterol that is carried in low density lipoproteins (LDL). However, not all cholesterol is bad. A proportion of the cholesterol in blood is carried in high density lipoproteins (HDL), which are powerful protectors against atherosclerosis. As not all HDL protect equally well against atherosclerosis, it ....Atherosclerosis is a major cause of death and disability in Australia. A high level of blood cholesterol increases the risk of developing atherosclerosis. This increase in risk is caused by the cholesterol that is carried in low density lipoproteins (LDL). However, not all cholesterol is bad. A proportion of the cholesterol in blood is carried in high density lipoproteins (HDL), which are powerful protectors against atherosclerosis. As not all HDL protect equally well against atherosclerosis, it is important to know how blood levels of HDL are regulated. In 1999 a new enzyme called endothelial lipase was discovered. Endothelial lipase dramatically decreases HDL levels in mice. The reason why this happens is not known. The main aims of this project are to work out how endothelial lipase decreases HDL levels and whether it decreases the levels of all HDL equally or whether it preferentially decreases the levels of certain types of HDL. The outcome of this project will establish how endothelial lipase affects the ability of HDL to protect against atherosclerosis in humans.Read moreRead less
Investigating The Mechanisms Of Regulation Of Mycobacterial Cell Wall Biosynthesis
Funder
National Health and Medical Research Council
Funding Amount
$597,349.00
Summary
Tuberculosis (TB) kills around two million people each year while the causative bacterial species, Mycobacterium tuberculosis, infects one-third of the entire human population. An alarmingly high rate of TB exists in Australia's indigenous population. This proposal aims to identify and characterise essential processes involved in synthesis of the outer coat of the bacterium which are potential targets for new drugs for the treatment of this devastating disease.
The Activation Of Lipoprotein Lipase By Apolipoprotein C-II
Funder
National Health and Medical Research Council
Funding Amount
$250,500.00
Summary
Abnormalities in blood lipid levels are common in our society. Treatment of these conditions adds a heavy burden to national health-care costs. Lipoprotein lipase is a plasma enzyme that plays a central role in maintaining safe blood lipid levels. The action of lipoprotein lipase in subjects on a western diet leads to the hydrolysis of about 150g of plasma triacylglycerol daily. Naturally occurring mutations in lipoprotein lipase, associated with a complete loss of enzyme activity, result in a h ....Abnormalities in blood lipid levels are common in our society. Treatment of these conditions adds a heavy burden to national health-care costs. Lipoprotein lipase is a plasma enzyme that plays a central role in maintaining safe blood lipid levels. The action of lipoprotein lipase in subjects on a western diet leads to the hydrolysis of about 150g of plasma triacylglycerol daily. Naturally occurring mutations in lipoprotein lipase, associated with a complete loss of enzyme activity, result in a high blood-lipids that can lead to premature atherosclerosis. Regulation of lipoprotein lipase occurs via an interaction with the regulatory protein apolipoprotein C-II. Individuals with apolipoprotein C-II deficiency also exhibit abnormal plasma lipid levels with an associated increased risk of coronary heart disease. These considerations demonstrate that the activation of lipoprotein lipase by apolipoprotein C-II is pivotal to the maintenance of normal blood lipid levels. The present proposal will establish the structure and orientation of apolipoprotein C-II in a lipid environment and provide a structural model for the activation of lipoprotein lipase by apolipoprotein C-II. These molecular details will serve as a model for the regulatory interactions of other apolipoproteins within lipoprotein particles and will generate leads for the development of new strategies for the treatment of blood lipid irregularities.Read moreRead less
Modulating Neuronal Secretion By The PI3-kinase Pathway
Funder
National Health and Medical Research Council
Funding Amount
$516,855.00
Summary
Neuronal communication relies on the process of exocytosis by which neurons release neurotransmitter. Exocytosis is critical for the simplest reflex movement to complex tasks such as learning and memory, and is altered in several neurodegenerative pathologies. We will investigate how certain lipids control exocytosis. This research is important for understanding how neurons communicate in health and disease and is relevant to other processes such as insulin release in diabetes.
Molecular Mechanisms Of Persistence Of Mycobacterium Tuberculosis
Funder
National Health and Medical Research Council
Funding Amount
$398,142.00
Summary
Mycobacterium tuberculosis is the bacterium that causes tuberculosis (TB. It infects about third of all people in the world and kills several million people each year. People with active TB spread the mycobacteria in aerosols from their breath. When another person inhales an infected aerosol the mycobacteria enter their lungs and establish a new infection. During the course of infection M. tuberculosis is exposed to a variety of harsh environments inside the lungs which normally kill other bacte ....Mycobacterium tuberculosis is the bacterium that causes tuberculosis (TB. It infects about third of all people in the world and kills several million people each year. People with active TB spread the mycobacteria in aerosols from their breath. When another person inhales an infected aerosol the mycobacteria enter their lungs and establish a new infection. During the course of infection M. tuberculosis is exposed to a variety of harsh environments inside the lungs which normally kill other bacteria. M. tuberculosis is able to survive and adapt to those harsh environments. M. tuberculosis has an especially thick and tough cell wall which protects it. M. tuberculosis can adapt to the environments it encounters in a patient by changing their cell walls. The wall also protects mycobacteria from chemicals so it is resistant to many common antibiotics. There are some drugs to treat TB however M. tuberculosis is building up resistance to those drugs so we need to find new ones We will determine how mycobacteria synthesize their special cell wall and how they adapt during an infection. If we know how the details of how M. tuberculosis protects itself then we can find potential weakness which could be targets for the development of new drugs to treat TB.Read moreRead less
Novel Upstream Regulatory And Down-stream Signaling Mechanisms Of The Src-family Protein Kinases
Funder
National Health and Medical Research Council
Funding Amount
$363,639.00
Summary
Normal cell growth and division are governed by the balanced action of two groups of enzymes - the enzymes encoded by the proto-oncogenes (precursors of cancer-causing genes) and the tumour suppressor genes. Abnormalities in the regulation of these enzymes cause cancer. Indeed, over-stimulation of a group of proto-oncogenic enzymes called the Src-family kinases (SFKs) is the major contributing factor to most human cancers. In this application, we propose to study how inactivation of SFKs by thei ....Normal cell growth and division are governed by the balanced action of two groups of enzymes - the enzymes encoded by the proto-oncogenes (precursors of cancer-causing genes) and the tumour suppressor genes. Abnormalities in the regulation of these enzymes cause cancer. Indeed, over-stimulation of a group of proto-oncogenic enzymes called the Src-family kinases (SFKs) is the major contributing factor to most human cancers. In this application, we propose to study how inactivation of SFKs by their native inhibitor CHK suppresses cancer formation and how over-stimulation of SFKs causes cancer. Exactly how CHK inactivates SFKs remains unclear. Recently, we discovered a novel mechanism employed by CHK to inhibit SFKs. In this mechanism, CHK binds to SFKs tightly and the binding alone is sufficient to completely shut down SFK activity. As this novel inhibitory mechanism of CHK can be exploited for the development of synthetic SFK inhibitors for cancer treatment, we propose to unravel how CHK tightly binds to SFKs and how the binding inhibits the cancer-promoting activity of SFKs. How over-stimulation of SFKs induces the development of human cancer has been an important outstanding question in cancer research. Recently, we and two groups of researchers in Texas achieved breakthroughs in answering this question. The Texan groups discovered that the over-stimulated SFKs cause cancer by shutting down the anti-tumour activity of a tumour suppressor called PTEN. We complemented their findings by discovering how SFKs shut down PTEN activity - SFKs shut down PTEN activity by a chemical modification process called phosphorylation. In this application, we propose to study how SFKs modify PTEN and how phosphorylation shuts down the tumour suppressor activity of PTEN. In summary, our studies will benefit the development of two types of anti-cancer therapeutics: (i) those mimicking CHK binding and inhibition of SFKs, and (ii) those interfering with phosphorylation of PTEN by SFKs.Read moreRead less
A Phase II Randomised Controlled Trial Of Atorvastatin Therapy In Intensive Care Patients With Severe Sepsis
Funder
National Health and Medical Research Council
Funding Amount
$622,148.00
Summary
Infections are common in patients in the intensive care unit and produce inflammation that may spread throughout the body. Despite improved therapies, when infections cause failure of the body's vital organs, up to 40% of patients may die. The medication atorvastatin and other statins have been used for many years to treat and prevent conditions such as heart attack and stroke. They act primarily by reducing cholesterol production. In addition, they also modify inflammation and the immune system ....Infections are common in patients in the intensive care unit and produce inflammation that may spread throughout the body. Despite improved therapies, when infections cause failure of the body's vital organs, up to 40% of patients may die. The medication atorvastatin and other statins have been used for many years to treat and prevent conditions such as heart attack and stroke. They act primarily by reducing cholesterol production. In addition, they also modify inflammation and the immune system which may make them a useful treatment for patients with established infections. Although the statin drugs are usually safe, rare side effects may affect muscle and the liver. Because of concerns about increased risk of side effects it is currently recommended that statins should be stopped when patients become unwell. However, a number of studies have suggested that patients on statins for heart disease are less likely to develop infections and that their infections are less likely to be severe or result in death. Other studies have suggested that stopping statins in patients that present with infections (as suggested by current guidelines), may worsen infection outcomes. However, these studies have not been detailed enough to exclude all factors affecting outcome, such as patient age, severity of the infection, and the presence of other diseases. We plan to perform a study to assess the effect of atorvastatin on the outcome of infections in the intensive care unit. We will study 250 patients presenting with severe infections. We will randomly assign patients to receive either atorvastatin or placebo and monitor the effect on signs of inflammation and levels of life support. Outcomes and side effects will be carefully monitored. The study will help us decide whether to perform a larger study to determine if atorvastatin can reduce the risk of dying from serious infections.Read moreRead less
Identification And Characterization Of Novel PI3-kinase Signal Transducing Elements In Platelets
Funder
National Health and Medical Research Council
Funding Amount
$457,500.00
Summary
Platelets play an important role in blood clotting and blood vessel repair. Upon vessel injury, platelets rapidly adhere to the site of damage where they undergo dramatic shape change to spread over the site of injury. Activation and regulation of these processes relies on a complex network of signal transduction processes, involving the integration of multiple receptors and pathways. One pathway demonstrated to play a role in regulating platelet responses is the enzyme phosphatidylinositol 3-ki ....Platelets play an important role in blood clotting and blood vessel repair. Upon vessel injury, platelets rapidly adhere to the site of damage where they undergo dramatic shape change to spread over the site of injury. Activation and regulation of these processes relies on a complex network of signal transduction processes, involving the integration of multiple receptors and pathways. One pathway demonstrated to play a role in regulating platelet responses is the enzyme phosphatidylinositol 3-kinase (PI3-kinase) and its lipid products PtdIns(3,4,5)P3 and PtdIns(3,4)P2. However, very little is known about exactly how PI3-kinase and its products regulate the platelet responses. Our research studies aim to gain a deeper understanding into the molecular mechanisms of PI3-kinase signal transduction in platelets, through the identification and characterization of novel platelet proteins that bind to PI3-kinase lipid products, and to define what role these proteins play in platelet PI3-kinase dependent responses.Read moreRead less
Genetic And Biochemical Analysis Of The PIM/LAM Biosynthetic Pathway In Mycobacteria.
Funder
National Health and Medical Research Council
Funding Amount
$272,250.00
Summary
Tuberculosis (TB) is one of the most devastating diseases in human history. TB kills approximately two millions people each year worldwide, more than any other disease caused by a single infectious agent. The disease has re-emerged in recent years due to the AIDS epidemic and the appearance of TB bacteria that are not killed by currently available antibiotics. New antibiotics must be developed to combat this global health threat. This requires the identification of targets on the bacteria on whi ....Tuberculosis (TB) is one of the most devastating diseases in human history. TB kills approximately two millions people each year worldwide, more than any other disease caused by a single infectious agent. The disease has re-emerged in recent years due to the AIDS epidemic and the appearance of TB bacteria that are not killed by currently available antibiotics. New antibiotics must be developed to combat this global health threat. This requires the identification of targets on the bacteria on which antibiotics can act. One particularly attractive target is the outer coat of the bacterium. Several existing antibiotics target the bacterial coat, yet the ways in which coat is assembled are poorly understood. Two related compounds in the bacterial coat, and unique to TB bacteria, are called PIMs and LAMs. The structures of these compounds are known, and the compounds appear to be essential for the survival of the bacteria in the human host. However, the mechanisms by which PIMs and LAMs are made by the bacteria are very poorly understood. The aim of our research proposal is to better understand the process by which these compounds are made. If this process can be blocked by an antibiotic, then this represents a potential anti-TB therapy which could save millions of lives worldwide.Read moreRead less
Role Of An Endogenously Synthesised Sterol In Regulating Cholesterol Removal From The Macrophage
Funder
National Health and Medical Research Council
Funding Amount
$276,000.00
Summary
Heart disease remains the greatest killer of Australians and involves accumulation of cholesterol in the artery wall. Cholesterol accumulates in a specific cell-type called the macrophage (literally means ' big-eater'). Once macrophages accumulate cholesterol, they become bloated cholesterol-filled foam cells. The early and persistent appearance of foam cells in diseased artery suggests that foam cells are active participants in the development of heart disease. Prevention or reversal of their f ....Heart disease remains the greatest killer of Australians and involves accumulation of cholesterol in the artery wall. Cholesterol accumulates in a specific cell-type called the macrophage (literally means ' big-eater'). Once macrophages accumulate cholesterol, they become bloated cholesterol-filled foam cells. The early and persistent appearance of foam cells in diseased artery suggests that foam cells are active participants in the development of heart disease. Prevention or reversal of their formation is therfore an attractive target for new therapies to treat heart disease. In this proposal, we address specific questions which will increase our understanding of how best to prevent or reverse foam cell formation. This work may indicate new therapeutic possibilities for combating heart disease.Read moreRead less