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
A Randomised Trial Of The Effects Of Cholesterol Lowering Therapy Among Patients With Chronic Renal Impairment
Funder
National Health and Medical Research Council
Funding Amount
$333,250.00
Summary
People with kidney disease are well known to be at high risk of developing major health problems earlier in life than people without kidney problems. In particular, people with kidney disease are more likely to suffer from heart attacks and strokes. For a number of other high-risk patient groups (such as people with heart disease), studies have clearly shown that cholesterol-lowering treatment can significantly reduce the risks of serious complications. However, until now, patients with kidney d ....People with kidney disease are well known to be at high risk of developing major health problems earlier in life than people without kidney problems. In particular, people with kidney disease are more likely to suffer from heart attacks and strokes. For a number of other high-risk patient groups (such as people with heart disease), studies have clearly shown that cholesterol-lowering treatment can significantly reduce the risks of serious complications. However, until now, patients with kidney disease have generally been excluded from such studies because of concerns about drug side effects. New, better-tolerated cholesterol lowering drugs now offer an opportunity to see if this highly effective treatment is also protective among people with kidney disease. The HARP (Heart And Renal Protection) trial is a large new study that will be done as a collaboration between Australian researchers and researchers from the University of Oxford in the UK. The aim of the study is to see if low doses of two cholesterol-lowering drugs can reduce the risks of stroke and heart attack. The study will include about 9,000 people with chronic kidney disease followed for an average of 4 years. It is hoped that by using low doses of two treatments, rather than a high dose of one, it will be possible to get substantial benefits without side effects. There are presently many tens of thousands of individual in Australia with chronic kidney disease and many millions of such individuals worldwide. The results of the HARP study will therefore influence the care of a very large number of people. If the results were positive, implementation of this new treatment would be expected to prevent many tens of thousands of premature strokes and heart attacks around the world each year.Read moreRead less
Improving Patient Outcomes In Familial Hypercholesterolaemia Across The Continuum Of Care
Funder
National Health and Medical Research Council
Funding Amount
$645,205.00
Summary
'Familial' means it runs in families and 'hypercholesterolaemia' means high blood cholesterol. Familial Hypercholesterolaemia (FH) is the most common and serious form of inherited high cholesterol. People with FH are at an increased risk of developing cardiovascular disease. High cholesterol also placed an estimated $4 billion burden on the Australian economy in 2017-18. Practical research on prevention strategies will improve cardiovascular health outcomes and lower the burden of health costs.
MECHANISTIC ROLE OF CHOLESTEROL IN NON-ALCOHOLIC STEATOHEPATITIS
Funder
National Health and Medical Research Council
Funding Amount
$533,541.00
Summary
Fatty liver is present in 15-30% of Australians, related to obesity, diabetes and heart attack. Two-thirds of cases reverse easily. The remainder evolve to non-alcoholic steatohepatitis (NASH), liver damage that can lead to cirrhosis and liver failure. This research seeks to find out why some cases of fatty liver lead to NASH, and whether cholesterol that accumulates in the livers of mice with NASH is what causes that damage. If so, we will find new ways to treat NASH by diet or drugs.
Modulation Of Cell Phospholipids And Membranes By 7-ketocholesterol And Their Role In Cholesterol Efflux.
Funder
National Health and Medical Research Council
Funding Amount
$186,372.00
Summary
Atherosclerosis is a leading cause of death in Australia. The disease is caused by the formation of large deposits of cholesterol in the walls of major blood vessels. This cholesterol comes from cholesterol-carrying particles in the blood which penetrate into the tissue of the blood vessel. They are taken up by the cells of the tissue which become engorged with large amounts of cholesterol and are called 'foam cells'. These foam cells also contain a small but signficant amount of damaged (oxidis ....Atherosclerosis is a leading cause of death in Australia. The disease is caused by the formation of large deposits of cholesterol in the walls of major blood vessels. This cholesterol comes from cholesterol-carrying particles in the blood which penetrate into the tissue of the blood vessel. They are taken up by the cells of the tissue which become engorged with large amounts of cholesterol and are called 'foam cells'. These foam cells also contain a small but signficant amount of damaged (oxidised) forms of cholesterol, called oxysterols. We have found than an oxysterol called 7-ketocholesterol makes it difficult for cells to get rid of excess cholesterol. Therefore this oxysterol may be part of the reason why foam cells develop. This project will study how 7-ketocholesterol blocks cholesterol removal from cells. This may lead to the development of drugs which remove or prevent 7-ketcholesterol accumulation in the blood vessel and so prevent or reverse atherosclerosis.Read moreRead less
Ras Signalling And Cholesterol Efflux From Late Endosomes
Funder
National Health and Medical Research Council
Funding Amount
$276,598.00
Summary
Accumulation of cholesterol is a hallmark of early atherosclerotic lesions, known as foam cell formation. Hence the stimulation of cholesterol removal (efflux) from macrophages has great therapeutic potential. High Density Lipoproteins (HDL) and apolipoprotein A-I (apoA-I) stimulate efflux via activation of HDL-apoA-I receptors and poorly understood signalling pathways. This application is investigating the role of the Ras-MAPK signalling pathway in promoting efflux from late endosomes.
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
Atherosclerosis: Lipoproteins, Cell Biology And Vascular Physiology
Funder
National Health and Medical Research Council
Funding Amount
$10,461,682.00
Summary
The world is confronting a major new epidemic of premature heart disease that is being driven by a global increase in obesity. There are several factors that contribute to the increased risk of heart disease in overweight and obese people. One is a low blood level of the “good” HDL cholesterol that normally protects against heart disease. Another relates to a decreased ability to remove cholesterol from the walls of arteries where it builds up to cause heart disease. A third is the fact that obe ....The world is confronting a major new epidemic of premature heart disease that is being driven by a global increase in obesity. There are several factors that contribute to the increased risk of heart disease in overweight and obese people. One is a low blood level of the “good” HDL cholesterol that normally protects against heart disease. Another relates to a decreased ability to remove cholesterol from the walls of arteries where it builds up to cause heart disease. A third is the fact that obesity is associated with a state of chronic inflammation of the blood vessels. This inflammation not only accelerates the development of heart disease but also makes people who have cholesterol accumulated in their arteries more likely to actually have a heart attack. And a fourth is the fact that the lining of blood vessels does not function normally in overweight and obese people. This loss of normal function is a very early sign of future heart disease. These factors are closely inter-related, with the “good” HDL playing a central role in removing cholesterol from arteries, inhibiting arterial inflammation and promoting normal function and repair of the lining of blood vessels. HDL is complex, consisting of a mixture of several subpopulations of particles that vary in shape, size and composition. Furthermore, these HDL subpopulations are continually remodelled as they circulate in blood in reactions promoted by a number of blood factors that change their size and composition. A major component of the research to be conducted in this program relates to understanding how the HDL subpopulations in human blood are regulated and how they protect against heart disease. The applicants have already made major contributions to understanding the functions of the “good” HDLs, how they take cholesterol out of cells in the artery wall, how they inhibit inflammation of the arteries and how they improve the function of the artery lining. We propose to extend these studies to establish how these protective functions can be enhanced, to find out which of the HDL subpopulations are most protective, and to identify how to increase the most protective HDLs in people at risk of heart disease.Read moreRead less