ABCA1 _ An Intersection Between Infection, Atherosclerosis And Metabolic Disorders
Funder
National Health and Medical Research Council
Funding Amount
$653,827.00
Summary
Pathogens interfere with cellular cholesterol metabolism in order to support their lifecycle. Such interference may cause diseases not usually associated with infection, like cardiovascular disease. Restoring normal cholesterol metabolism may help treating infection and its metabolic consequences. We will investigate molecular, cellular and physiological mechanisms of interaction of pathogens with cholesterol metabolism to find a key point that can be targeted for therapeutic intervention.
Lipoprotein Metabolism And Mutations Of The APOB Gene Causing Familial Hypobetalipoproteinaemia
Funder
National Health and Medical Research Council
Funding Amount
$396,179.00
Summary
Cardiovascular disease is an increasing problem in Australia, however, the cause of atherosclerosis is incompletely understood. A protein, known as apolipoprotein (apo) B, plays a central role in lipoprotein metabolism. Elevated levels of apoB are characteristic of many forms of hypercholestrolaemia. Familial combined hyperlipidaemia and polygenic hypercholesterolaemia are two common inherited disorders of lipoprotein metabolism that are characterised by elevated apoB levels in the blood and ear ....Cardiovascular disease is an increasing problem in Australia, however, the cause of atherosclerosis is incompletely understood. A protein, known as apolipoprotein (apo) B, plays a central role in lipoprotein metabolism. Elevated levels of apoB are characteristic of many forms of hypercholestrolaemia. Familial combined hyperlipidaemia and polygenic hypercholesterolaemia are two common inherited disorders of lipoprotein metabolism that are characterised by elevated apoB levels in the blood and early atherosclerosis. In contrast, familial hypobetalipoproteinemia is a rare inherited disorder of lipoprotein metabolism characterised by very low levels of cholesterol and apoB in the blood and resistance to atherosclerosis and cardiovascular disease. The focus of this research project is to explore the regulation of apoB metabolism using individuals from unique families with familial hypobetalipoproteinaemia. First, we will determine and characterise the alterations in the APOB gene causing the low cholesterol levels in families with familial hypobetalipoproteinaemia. Second, we will determine if these apoB alterations affect the production and-or clearance of blood fats, or lipoproteins in affected individuals, when compared to controls, by performing metabolic studies. The proposed human in vivo metabolic studies will lead to a better understanding of the mechanism(s) involved in the assembly, secretion, transport, and clearance of plasma apoB-containing lipoproteins. Furthermore, these studies may reveal new protective mechanisms and potentially aid in the development of strategies to suppress over-production of apoB-containing lipoproteins in reciprocal conditions such as familial combined hyperlipidaemia or polygenic hypercholesterolaemia.Read moreRead less
Identifying A Novel Role For Pigment Epithelium-derived Factor In Obesity-related Metabolic Dysfunction
Funder
National Health and Medical Research Council
Funding Amount
$361,637.00
Summary
Obesity is an important factor contributing to insulin resistance and type 2 diabetes; however, the factors linking these disorders are not well defined. A protein called PEDF is elevated in obesity and type 2 diabetes. This project will examine how PEDF causes insulin resistance and whether blocking PEDF's actions prevents insulin resistance. Successful completion of this project may lead to therapeutics that reduce the risk of developing type 2 diabetes.
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
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.
Niemann Pick Disease Type C And Intracellular Sterol Trafficking
Funder
National Health and Medical Research Council
Funding Amount
$317,741.00
Summary
Abnormal distribution of cellular cholesterol causes Nieman Pick Disease type C (NP-C), and is also strongly associated with common neurodegenerative diseases such as Alzheimer's disease. We aim to understand the molecular mechanisms by which cholesterol is sorted and transported in the cell. Our results may help develop effective therapeutic strategies against NP-C, Alzheimers' disease and other cholesterol related disorders.
Brown fat protects animals against obesity and diabetes. Humans with abundant brown fat are metabolically healthy. Identification of medication that boosts brown fat function may lead to novel treatment of metabolic disorders. This proposal will examine the role of such a medication, which is modeled on a factor (called FGF21) released from brown fat. The project will also search for other factors released by human brown fat, which may become future targets of obesity treatment.
Defining The Function Of Apolipoprotein-D In Alzheimer's Disease
Funder
National Health and Medical Research Council
Funding Amount
$457,231.00
Summary
Alzheimer's disease (AD) prevalence is rising and there is no curative treatment. Neurotoxic amyloid-beta peptide and concomitant lipid oxidation in the brain contribute to the cause of AD. We have identified a new pathway by which a protein called apoD may inhibit lipid oxidation in the AD brain. We will test the impact that changing apoD levels in neurons and in genetically modified mice has on neuron stress and AD-like characteristics. This may reveal new avenues to prevent or treat AD.
Modulating Inflammation As A Therapy For Harlequin Ichthyosis
Funder
National Health and Medical Research Council
Funding Amount
$718,739.00
Summary
Harlequin Ichthyosis is a severe inherited skin disease caused by mutations in a protein which regulates how skin cells control their levels of lipids. Treatments for this disease are limited and do little to improve patients condition. We believe we have found a new way to treat this condition by altering tissue inflammation. This grant will undertake important experiments aimed at developing new therapies for this currently incurable disease.
Molecular Mechanisms Of Inherited Hypocholesterolaemias: Impact Of APOB And MTTP Mutations On Lipoprotein Assembly And Secretion
Funder
National Health and Medical Research Council
Funding Amount
$200,213.00
Summary
Inherited low cholesterol levels can be caused by mutations in either of two genes: APOB and MTTP. These genes encode proteins that are critical for the assembly of fat particles in the body. We plan to use cell lines to study how single amino acid changes out of the 4500 in ApoB and the 900 in the MTTP protein affect protein production, binding with other proteins, and fat particle assembly.