The theme of this proposal is the examination of altered states of triglyceride metabolism contributing to coronary artery disease. The program addresses this theme using the mouse and human homology at the pathological, physiological, biochemical, genomic and molecular levels. Of the 5 projects in this proposal, Projects 3 will mostly involve studies in mice while 2 projects principally involve studies in humans, with 5 cores providing phenotyping, genotyping, sequencing, positional cloning, biostatistical and administrative support. Our major approach will be use genetic defects in mice and humans to identify underlying genes that contribute to altered states of triglyceride metabolism. We will emphasize familial combined hyperlipidemia (FCHL), a genetically complex disease characterized by increased plasma triglyceride metabolism. We will emphasize familial combined hyperlipidemia (FCHL), a genetically complex disease characterized by increased plasma triglyceride and/or cholesterol levels which accounts for up to 20% of premature coronary artery disease. Dr. Lusis' project will extend previous genetic studies in mice to systematically delineate genetic factors contributing to triglyceride metabolisms. Notably, will combine forces with Dr. Peltonen's Project to identify the gene affected by Hyplip1, a mutation in the mouse that causes combined hyperlipidemia and co- localizes with a homologous FCHL locus in humans. Dr. Wong's Project will focus on the structure-function properties of lipoprotein lipase (LPL), an enzyme central to triglyceride metabolism, as well as identifying genetic loci that affect LPL expression and may contribute to the LPL deficiency observed in FCHL. Dr. Reve's Project will isolate the genes, and characterize the function of the corresponding gene products, for two mouse mutations affecting triglyceride metabolism, fatty liver dystrophy (fld) and combined lipase deficiency (cld); these mutations are characterized by insulin resistance (fld) and LPL deficiency (cld) that often associated with FCHL. Dr. Rotter's project will use a combination of genome wide linkage and candidate gene association approaches to characterize genetic risk factors for coronary artery disease in human populations by identifying genes for lipid and lipoprotein variation in FCHL. Dr. Peltonen's project, using the power of a discrete population isolate (the Finn's) will perform fine mapping of a recently identified FCHL locus to isolate the predisposing FCHL gene by a positional cloning approach. Importantly, the Finnish FCHL locus is syntenic with mouse Hyplip1, and Project V will assist in isolating the mouse gene to complement and aid in the identification of the homologous human FCHL gene. Thus, the 5 projects provide a coordinated approach to identifying major genes affecting triglyceride metabolism and predisposing to coronary artery disease.
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