Premature vascular disease in young hyperlipidemic subjects remains a major unsolved health problem in terms of pethogenesis and treatment. Recent research has made available reference values for diagnosing hyperlipidemia, markers for genetic analysis, and methods for studying lipoprotein metabolism and arteriosclerotic disease progression. With these advances, the opportunity now exists for in depth, focused studies of lipoprotein pathophysiology in genetically characterized patients toward the objective of understanding disease mechanisms and developing better treatments. This program in """"""""Human Lipoprotein Pathophysiology"""""""" siezes this opportunity with 8 coordinated projects and 4 supporting core laboratories led by experienced investigators, experts in physiology, genetics, biochemistry, immunochemistry, metabolism nutrition, and cardiology. Subjects will be characterized in terms of the heritability of lipoprotein abnormalities, the metabolism of lipoproteins, including carefully characterized subpopulations of HDL isolated by immunoabsorption. The role of LCVAT and lipid transfer proteins in the genetic hyperlipidemics will be studied and related to the kinetic abnormalities of lipoprotein metabolism in vivo. The fate of lipoproteins will be studies in human cultured macrophages and placental trophoblast cells and will further the understanding the role of macrophages and steroid hormone secreting cells in lipoprotein homeostasis and atherosclerosis. The effects of diet and drug interventions will also be studied including the effects of omega-3 fatty acid feeding on lipoprotein lipid metabolism and effects of diet and drug lowering of lipoprotein on arteriosclerosis. This work will be supported by excellent Core facilities in lipoprotein measurement, apoprotein immunoassay, and biomathematical analysis and offers promise of rapid progress in understanding mechanisms and providing treatrment for the premature vascular diseade associated with genetic hyperlipidemia.
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