Inflammatory disorders a variety of pathologies, besides septicemia, infections and non-infective diseases, also are implication in metabolic disorders, such as type 2 diabetes (T2D) and hypercholesterolemia . Activin A is a protein that has important effects in inflammatory disorders. Because T2D and hypercholesterolemia have inflammatory characteristics and activin A has important effects in inflammatory disorders, it merits studying the links between activin A, T2D and hypercholesterolemia.
Aberrant Oligosaccharide Processing Of Nox2-oxidase As A Mechanism Of Vascular Oxidative Stress In Atherosclerosis
Funder
National Health and Medical Research Council
Funding Amount
$552,565.00
Summary
Excessive production of free radicals by an enzyme called Nox2 may be a cause of artery disease leading to heart attacks and strokes. This study will identify whether the addition of sugarchains to Nox2 causes it to be expressed at the surface of cells allowing the free radicals it produces to exit the cell and cause damage to the blood vessel wall. Charaterising this new pathway of excessive free radical production may pave the way for new diagnostics and treatments for artery disease.
We propose to study the poorly understood, disease-associated process of amyloid formation, using a sensitive and reproducible model developed in our laboratory. Amyloid deposits are a feature of several neurodegenerative and metabolic disorders such as Alzheimer's and Parkinson's disease and are also common in atherosclerotic plaque or atheroma. They are composed of tangled networks of fibrillar proteins together with several non-fibrillar proteins and proteoglycans. Atherosclerotic plaques typ ....We propose to study the poorly understood, disease-associated process of amyloid formation, using a sensitive and reproducible model developed in our laboratory. Amyloid deposits are a feature of several neurodegenerative and metabolic disorders such as Alzheimer's and Parkinson's disease and are also common in atherosclerotic plaque or atheroma. They are composed of tangled networks of fibrillar proteins together with several non-fibrillar proteins and proteoglycans. Atherosclerotic plaques typically consist of fibrous proteins, lipids and foam cells derived from macrophages via receptor-mediated uptake of oxidized low density lipoproteins. Our model system is based on the formation of amyloid fibrils from apolipoprotein (apo) C-II which accumulates in atherosclerotic plaques where it co-localizes with serum amyloid P component, a marker of amyloid fibrils. ApoC-II is a component of plasma lipoproteins and an important activator of the enzyme lipoprotein lipase, which functions in the transport and distribution of triacylglycerols to tissues. We have shown that apoC-II (79 amino acids) readily forms amyloid fibrils under lipid-free conditions, adopting a cross-beta sheet structure that reacts with the amyloid stains thioflavin T and Congo Red. The formation and properties of apoC-II amyloid fibrils and the amyloid-like properties of oxidized lipoproteins are the subject of the present proposal. We will characterize the effects of lipids and oxidation on the rate of formation and the properties of apoC-II amyloid fibrils. We will also study the effects of oxidation on the amyloid-like properties of lipoproteins and their interactions with serum amyloid P component and cell surface receptors.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
The Structural Basis For Amyloid Formation By Human Apolipoproteins
Funder
National Health and Medical Research Council
Funding Amount
$210,990.00
Summary
Amyloid formation is considered an abnormal state of protein aggregation that accompanies numerous medical conditions, notably Alzheimer disease, Parkinson's disease, the transmissible spongiform encephalopathies (e.g. scrapie, Creutzfeldt-Jakob disease) and metabolic diseases such as diabetes. These diseases involve a variety of normally non-fibrillar proteins with at least 20 human proteins identified as components of different types of amyloid. The current wide publicity given to bovine spong ....Amyloid formation is considered an abnormal state of protein aggregation that accompanies numerous medical conditions, notably Alzheimer disease, Parkinson's disease, the transmissible spongiform encephalopathies (e.g. scrapie, Creutzfeldt-Jakob disease) and metabolic diseases such as diabetes. These diseases involve a variety of normally non-fibrillar proteins with at least 20 human proteins identified as components of different types of amyloid. The current wide publicity given to bovine spongiform encephalopathy (BSE) disease and the potential impact on human health highlights the importance of developing strategies for treating these conditions. The prevalence of apolipoproteins in atherosclerotic amyloid deposits and senile plaques suggests a general propensity for human apolipoproteins to form pathogenic amyloid fibrils. Our recent observations that lipid-free human apolipoprotein C-II (apoC-II) forms ribbon-like fibrils in vitro provides an experimental system to explore this phenomenon. We propose to determine the structural requirements for the formation of amyloid fibrils human apoC-II and whether lipid-free human apolipoproteins form mixed-amyloid fibrils. Future strategies for treatment require better information on amyloid structure, the potential for mixed amyloid formation and the role of in vivo factors such as lipids and macromolecular crowding in regulating amyloid growth.Read moreRead less