The theme of this investigation is the hypothesis that insulin resistance (IR), hyperinsulinemia and a subset of components of the IR syndrome promote changes in the vasculature leading to atherosclerosis, and that there are common genes linking these factors and coronary artery disease (CAD). We have developed a multi-disciplinary approach incorporating gene mapping in animals and in man with human and animal physiologic analyses that involve extensive phenotyping of traits related to IR and atherosclerosis to test this hypothesis, Because of their family structure and the high prevalence of IR, Mexican American (MA) families with CAD represent an ideal ethnic group in which to identify genes linking to both IR and CAD and to determine the critical physiologic relationships of IR and hyperinsulinemia and its associated metabolic changes to vascular structural alterations leading to atherosclerosis. Exciting preliminary data in MA families supports both our hypothesis and the overall feasibility of completing the goals outlined in this grant application. Three experienced teams of senior research investigators and three supportive cores constitute a highly focused, collaborative, integrated investigation that features expertly designed and performed phenotyping; innovative methods of mathematical genetic analysis pioneered and successfully applied by members of our team; state of the art genetic mapping technology through the newly created UCLA Human Genetics Department; and physiologic investigation of the role of hyperinsulinemia and IR in atherosclerosis through novel mechanisms leading to vascular damage including the role of paraoxonase, hepatic lipase and alterations in lipid turnover, as well as lipid oxidation. An important theme of this program project is gene->cell->tissue->animal- >human->gene translation. The combination of detailed human and animal phenotyping, comprehensive genetic mapping, novel tissue investigations and lipid turnover studies outlined herein provides a powerful, multi- dimensional approach to identify genes and pathophysiologic mechanisms linked to atherosclerosis.
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