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
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
EXAMINING THE RELATIONSHIP BETWEEN MATRIPTASE-2 AND HEMOJUVELIN, TWO ESSENTIAL REGULATORS OF IRON HOMEOSTASIS
Funder
National Health and Medical Research Council
Funding Amount
$533,541.00
Summary
The control of iron levels is important in health and well being. Too little can lead to iron deficiency and anaemia, conversly too much can lead to haemochromatosis and tissue damage. We will examine the role of two proteins, matriptase-2 and hemojuvelin that when mutated cause iron deficiency or iron overload respectively. We will study how these proteins interact and work in opposite directions to control iron levels. The results will help to develop new therapeutics for iron disorders.
Atherosclerosis - The Key Roles Of HDL, Cell Cholesterol Metabolism And Vascular Function
Funder
National Health and Medical Research Council
Funding Amount
$7,085,050.00
Summary
Atherosclerosis, an accumulation of cholesterol in the artery wall, is a major cause of illness and premature death worldwide. It is caused by conditions such as low levels of the protective high density lipoproteins (HDLs), diabetes, smoking and abnormal function of arteries, all of which are linked to disorders of cholesterol metabolism. With our expertise in HDLs, cholesterol metabolism and artery function, our research will lead to the development of novel strategies for early detection and ....Atherosclerosis, an accumulation of cholesterol in the artery wall, is a major cause of illness and premature death worldwide. It is caused by conditions such as low levels of the protective high density lipoproteins (HDLs), diabetes, smoking and abnormal function of arteries, all of which are linked to disorders of cholesterol metabolism. With our expertise in HDLs, cholesterol metabolism and artery function, our research will lead to the development of novel strategies for early detection and prevention of atherosclerosis and heart disease.Read moreRead less
Characterising An Important Control Point In Cholesterol Synthesis Beyond HMG-CoA Reductase
Funder
National Health and Medical Research Council
Funding Amount
$480,739.00
Summary
The statins are the ‘go-to’ drugs for treating heart disease; blocking a very early, highly-controlled step in the pathway producing cholesterol. However, they inhibit the production of other vital molecules which explains why some patients do not tolerate them. We have identified that a later enzyme in this pathway is also highly controlled and here aim to characterise the molecular mechanisms involved. This work could translate into the development of even safer drugs for treating cholesterol- ....The statins are the ‘go-to’ drugs for treating heart disease; blocking a very early, highly-controlled step in the pathway producing cholesterol. However, they inhibit the production of other vital molecules which explains why some patients do not tolerate them. We have identified that a later enzyme in this pathway is also highly controlled and here aim to characterise the molecular mechanisms involved. This work could translate into the development of even safer drugs for treating cholesterol-related diseases.Read moreRead less
Our goal is to discover new mechanisms involved in our cells’ delicate balancing act with respect to cholesterol levels. Understanding how production of cholesterol is controlled in our cells is key to developing new drugs aimed at preventing its excessive accumulation. This will have long-term benefits for health considering that a cellular imbalance in cholesterol is involved in two of the most common conditions threatening the health of Australians, namely heart disease and Alzheimer’s diseas ....Our goal is to discover new mechanisms involved in our cells’ delicate balancing act with respect to cholesterol levels. Understanding how production of cholesterol is controlled in our cells is key to developing new drugs aimed at preventing its excessive accumulation. This will have long-term benefits for health considering that a cellular imbalance in cholesterol is involved in two of the most common conditions threatening the health of Australians, namely heart disease and Alzheimer’s disease.Read moreRead less
Deciphering Signalling Pathways Regulating Iron Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$407,402.00
Summary
Iron overload and anaemia are two of the most significant health problems affecting humans. Understanding how the body regulates iron levels is key to our understanding of these disorders and to the future development of new therapies. This research is aimed at understanding how a hormone produced in the liver called hepcidin that maintains iron balance is regulated. This research may lead to novel therapies aimed at correcting the iron balance in conditions of iron overload or anaemia.