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 1) the molecular, genetic, and pathophysiological basis of the inherited dyslipoproteinemias with particular reference to familial combined hyperlipidemia (FCHL), and on fundamental studies of lipoprotein physiology, particularly in regard to HDL, the proteins of lipid transport and macrophage-lipoprotein interactions. Subjects will be characterized in terms of the heritability of lipoprotein abnormalities, including apolipoprotein restriction fragment-length polymorphisms (Project 2) and the metabolism of the apoprotein B- containing lipoproteins, including precursor-product relationships (Project 1). Basic studies of lipoprotein physiology will include the structure, function and metabolism of HDL subclasses isolated by immunoaffinity chromatography (Project 4), and the role of lipid transfer proteins in modulating lipoprotein composition and intravascular lipoprotein metabolism (Project 3), Project 5 proposes to evaluate the mechanisms of oxidative modification of lipoproteins by cells, the uptake of modified lipoproteins by macrophages, the delivery of arachidonic acid to macrophages, and the definition of modulators of reverse cholesterol transport. The effects of diet and drug interventions on atherosclerosis progression/regression using quantitative coronary angiography will be evaluated in Project 8. Thus, in this Program Project, comprised of six coordinated projects and six supporting core laboratories, a multidisciplinary team of investigators will combine their expertise in physiology, molecular biology, biochemistry, genetics, immunochemistry, nutrition, endocrinology, metabolism, cardiology, epidemiology, and biomathematics, to study lipoprotein physiology and pathophysiology at several levels of biological organization from basic molecular and cell biology through in vivo studies in man to studies in populations.
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