Molecular genetics of cardioprotection

缺血性心脏病是非裔美国人的主要死亡原因。导致缺血性心脏病的两个危险因素高血压和胰岛素抵抗在非裔美国人群体中是一个重大的医疗问题。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)来定位导致心脏对缺血损伤敏感性增加的基因。我们的初步研究表明，采用多种独立的组织损伤指标，达尔·S(SS/MCW)大鼠的心脏对全球缺血的敏感性是布朗·挪威(BN/SSN/MCW)大鼠的两倍。我们假设遗传因素导致S(SS/MCW)大鼠比挪威棕色大鼠(BN/SSN/MCW)心肌缺血易感性增加。这一假设将在BN/SSN/mc2(血压正常、非胰岛素抵抗、抵抗心肌缺血的大鼠)和SS/mc2大鼠(高血压、胰岛素抵抗的大鼠)之间的杂交后代中得到验证，用于促进对近交系大鼠的缺血抵抗进行离散的、良好控制的研究。同源基因大鼠将被开发出来，以进一步降低复杂性，使其成为“单基因性状”。具体地说，我们将：(1)通过研究对单独缺血、对缺氧的适应和缺血前的预适应的反应，确定分离的心脏和冠状动脉与更长时间滞留的亲本株的表型差异。(2)定位心肌缺血易感基因(S)。在特定目的1中开发的表型方案将用于BN/SSN/MCW和SS/MCW杂交的300只动物的表型。全基因组扫描将被用来定位与此杂交中的缺血易感性有关的数量性状基因座(QTL)。在全基因组扫描中发现QTL的区域将通过比较图谱、使用开发的信息学工具和辐射杂交图谱转换为人类同源区域。(3)根据同源菌株对单纯缺血、低氧适应和缺血前预适应的反应，确定分离的心脏和血管的表型。这将有助于我们理解并有助于确定因果基因(S)。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，并将提供有望促进制定非裔美国人管理缺血性心脏病的策略的信息。

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.