MOLECULAR GENETIC APPROACHES IN ATHEROSCLEROSIS

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Molecular genetic approaches in atherosclerosis research is the theme of our Program Project which focuses on expression of genes involved in lipid transport and disease, including genes for apo B, for the lipases LPL and HL, for apo AIV, for the genes involved in the cld and fld defects in inbred mice, and many others. Five projects and five cores collaborate closely; research includes the latest techniques to "knock- out" genes, microsatellites to develop both mouse and human linkage maps for quantitative trait loci analysis, crystallization for 3 dimensional structure analysis, and transfection of primary hepatocytes to test the two-step model of lipoprotein assembly. Project I, ApoB: Genetic Polymorphism and Role in VLDL Biosynthesis, probes lipoprotein assembly at eh molecular level, and studies altered levels of the two different LDL in the serum of single individuals; Project II, Lipase Structure- Function, focuses on chimeric LPL and HL, lipase mutations and crystallization, Project III, Gene Determinants of Lipoprotein Expression: Mouse Model, is engaged in "knocking out" genes for apo A-II and apo A-IV, and quantitative trait loci studies in inbred mice; Project IV, Genetic Factors Contributing to CAD and their Risks, collects families with multiple incidence of CAD and uses human linkage maps constructed for these families to identify and characterize genes involved in atherosclerosis. Project V, Molecular Genetics of Lipase Expression, is focused on gene defects affecting lipase expression in the cld and fld mice. The supporting cores include Core A, lipoprotein and lipid analysis with robot assisted assays; Core B, quantitative trait loci and genetic markers; Core C, large scale expression; and Core D, lymphoblastoid cell lines. The disciplines of human and mouse genetics, molecular biology, biochemistry, biophysics and medicine are represented in these studies.