Molecular genetics of cardioprotection

心脏保护的分子遗传学

• 批准号: 6648592
• 负责人: JOHN E BAKER
• 金额: $ 32.87万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6648592
• 关键词: cytoprotection; genetic mapping; genetic strain; genetic susceptibility; hypertension; insulin sensitivity /resistance; isolation perfusion; laboratory rat; myocardial ischemia /hypoxia; quantitative trait loci

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.

缺血性心脏病是非裔美国人的主要死因。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）来定位负责增加心脏对缺血性损伤的敏感性的基因。我们的初步研究表明，在Dahl S（SS/Mcw）大鼠的离体心脏中，对全脑缺血的敏感性是使用多个独立的组织损伤测量的Brown Norway（BN/SsN/Mcw）大鼠心脏中的2倍。我们推测，遗传因素是负责增加心肌缺血的Dahl S（SS/Mcw）相比，布朗挪威（BN/SSN/Mcw）大鼠的易感性。将在BN/SsN/Mc 2（血压正常、非胰岛素抵抗大鼠，对心肌缺血具有抵抗性）和SS/Mc 2大鼠（高血压、胰岛素抵抗大鼠，用于促进近交系大鼠品系中对缺血的抵抗性的离散、良好对照研究）之间杂交的后代中检验该假设。同类大鼠将被开发，以进一步减少复杂性，以一个“单基因性状”。具体而言，我们将：（1）通过研究单独缺血、缺氧适应和缺血前预处理对离体心脏和冠状动脉的影响，确定在更长时间内与亲本株的表型差异。(2)绘制心肌缺血易感性基因图谱。在特定目标1中开发的表型分析方案将用于BN/SsN/Mcw和SS/Mcw杂交的300只动物的表型分析。将使用全基因组扫描来定位该杂交中负责缺血易感性的数量性状位点（QTL）。通过比较作图，利用发展中的信息学工具和辐射杂交作图，将在全基因组扫描中鉴定的具有QTL的区域转换为人类同源区域。(3)确定同种品系的离体心脏和血管对以下反应的表型：单独缺血、缺氧适应和缺血前预处理。这将有助于我们的理解，并帮助确定致病基因。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，并将提供预期有助于制定管理非洲裔美国人缺血性心脏病策略的信息。