Molecular genetics of cardioprotection

缺血性心脏病是非裔美国人死亡的主要原因。导致缺血性心脏病的两个危险因素，高血压和胰岛素抵抗是非洲裔美国人的一个重大医疗问题。我们的目标是使用胰岛素抵抗和高血压的动物模型（Dahl S大鼠）来绘制负责增加心脏对缺血性损伤敏感性的基因。我们的初步研究表明，通过多种独立的组织损伤测量，Dahl S （SS/Mcw）大鼠离体心脏对全身缺血的易感性是Brown Norway （BN/SsN/Mcw）大鼠心脏的两倍。我们假设遗传因素是导致Dahl S （SS/Mcw）比Brown Norway （BN/SsN/Mcw）大鼠对心肌缺血易感性增加的原因。这一假设将在BN/SsN/Mc2（一种血压正常、无胰岛素抵抗的大鼠，对心肌缺血有抵抗力）和SS/Mc2大鼠（一种高血压、胰岛素抵抗的大鼠，用于对近交系大鼠的缺血抵抗进行离散、良好控制的研究）的杂交后代中进行验证。基因大鼠将被开发，以进一步降低复杂性到“单基因性状”。具体而言，我们将：(1)通过研究对缺血的反应，对缺氧的适应和缺血前的预处理，确定离体心脏和冠状血管在更大程度上与亲本菌株的表型差异。(2)定位心肌缺血易感性基因。在Specific Aim 1中开发的表型方案将用于在BN/SsN/Mcw和SS/Mcw之间的杂交中对300只动物进行表型分析。全基因组扫描将用于绘制该杂交中负责缺血易感性的数量性状位点（qtl）。利用正在开发的信息学工具和辐射杂交作图，通过比较作图，将全基因组扫描中鉴定出的qtl区域转换为人类同源区域。(3)确定同源菌株离体心脏和血管在单独缺血、缺氧适应和缺血前预处理时的表型。这将促进我们的理解，并有助于确定致病基因。这些信息将为我们的临床项目提供候选基因组区域，并将有助于我们了解心肌缺血易感性的遗传基础，并将提供有望促进非裔美国人缺血性心脏病管理策略发展的信息。

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.