Premature vascular disease in young hyperlipidemic subjects remains a major unsolved health problem in terms of pathogenesis and treatment. Recent research advances have led to new markers for genetic analysis, new methods for studying lipoprotein metabolism and atherosclerotic disease progression and regression, and reference values for diagnosing hyperlipidemia. With these advances, the opportunity now exists for further in-depth focused studies of lipoprotein physiology and pathophysiology in genetically characterized patients with the objectives of understanding disease mechanisms, developing better treatments, and identifying and preventing early vascular disease. This will be accomplished by focusing our attention on the molecular, genetic and pathophysiological basis of the inherited dyslipoproteinemias associated with premature coronary artery disease with particular reference to familial combined hyperlipidemia, familial moderate hypercholesterolemia, familial elevation of Lp(a) and the carrier state for homocysteinemia. Coordinated studies of characterization of the pathophysiological state, the identification of possible molecular biological defects and the evaluation of these results in families by statistical genetic techniques will be performed in each disorder. The role of protein mediated intravascular modification of lipoproteins and the role of oxidation of lipoproteins in each disorder will lead to characterization of these genetic lipoprotein abnormalities. The Program Project, comprised of four coordinated projects, four supporting core facilities and a multidisciplinary team of investigators will combine the expertise in physiology, molecular biology, biochemistry, genetics, immunochemistry, nutrition, endocrinology, metabolism, epidemiology, and statistical genetics, to study lipoprotein physiology and pathophysiology at several levels of biological organization from basic molecular and cell biology through in vivo studies in humans to studies in populations.
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