Ischemic heart disease is the leading cause of death in African- Americans. Two of the risk factors that contribute to ischemic heart disease, hypertension and insulin resistance are a substantial medical problem in the African-American population. Our goal is to use an animal model of insulin resistance and hypertension (Dahl S rat) to map the genes responsible for increased sensitivity of the heart to ischemic injury. Our preliminary studies suggest that susceptibility to global ischemia in the isolated heart from Dahl S (SS/Mcw) rats is two-fold greater than in hearts from Brown Norway (BN/SsN/Mcw) rats using multiple independent measures of tissue injury. We hypothesize that genetic factors are responsible for increased susceptibility to myocardial ischemia in the Dahl S (SS/Mcw) compared with the Brown Norway (BN/SsN/Mcw) rat. This hypothesis will be tested in the progeny of a cross between the BN/SsN/Mc2 (a normotensive, non-insulin resistant rat, resistant to myocardial ischemia) and SS/Mc2 rat (a hypertensive, insulin resistant rat, used to facilitate discrete, well-controlled investigations of resistance to ischemia in the inbred rat strains. Congenic rats will be developed to further reduce the complexity to a """"""""single gene trait"""""""". Specifically we shall: (1) Determine the phenotypic differences of isolated hearts and coronary vessels from the parental strains in greater detain by studying the responses to: ischemia alone, adaptation to hypoxia and preconditioning prior to ischemia. (2) Map the gene(s) responsible for susceptibility to myocardial ischemia. The phenotyping protocol developed in Specific Aim 1 will be used to phenotype 300 animals in a cross between BN/SsN/Mcw and SS/Mcw. A total genome scan will be used to map the quantitative trait loci (QTLs) responsible for susceptibility to ischemia in this cross. Regions with QTLs identified in the total genome scan will be converted to the human homologous region by comparative mapping, using developing informatics tools and radiation hybrid mapping. (3) Determine the phenotype of isolated hearts and blood vessels from the congenic strains in response to: ischemia alone, adaptation to hypoxia, and preconditioning prior to ischemia. This will facilitate our understanding and help identify the causal gene(s). This information will provide candidate genome regions for our clinical projects, and will contribute to our understanding of the genetic basis underlying susceptibility to myocardial ischemia, and will provide information expected to facilitate the development of strategies to manage ischemic heart disease in African-Americans.
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