This SCOR proposes an integrated set of basic and clinical studies aiming to define molecular mechanisms of atherogenesis at the level of the arterial wall. Effects on atherogenesis of arterial wall enzymes, lipoproteins, diabetes and the immune system, and the interactions amongst these factors, will be investigated in induced mutant mouse models. A parallel set of studies in humans will determine the relevance of mechanisms defined in mice to the pathophysiology of human atherosclerosis and coronary heart diseases (CHD). Thus, the SCOR will define new mechanisms of atherogenesis and evaluate their significance in humans. Project 1 will assess the role of arterial sphingomyelinase and proteoglycans in arterial retention and aggregation of atherogenic lipoproteins and in atherogenesis. Project 2 will study the effects of arterial lipoprotein lipase on lipoprotein retention, macrophage functions and atherogenesis, and also the impact of human apoCIII gene variation on the arterial influx and atherogenicity of triglyceride-rich lipoproteins. Project 3 will determine the effects of cholesteryl ester transfer protein and high density lipoproteins on atherogenesis in mice and humans, and evaluate anti-atherogenic mechanisms involving reverse cholesterol transport of influx of atherogenic particles into arteries. Project 4 will evaluate the role of advanced glycosylation end products and their receptor on diabetic vasculopathy and atherogenesis, and develop a diabetic atherosclerotic mouse model. Project 5 will assess the role of gamma interferon and the immune system (lymphocyte subpopulations) in atherogenesis in mice and humans. The four cores will be A) administrative, B) clinical/Biostatistics, C) Molecular Biology and D) Pathology. The study and cross-breeding of induced mutant mice amongst different projects will be a unifying factor in the SCOR. Other unifying themes include the interactions of lipoproteins with the arterial wall, the effects of diabetes on atherosclerosis, and the influence of human genetic variation on CHD. The studies are likely to provide new therapeutic targets in atherosclerosis and novel genetic information on CHD risk that complements traditional lipoprotein measurements.
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