GENETICS AND INTERMITTENT MYOCARDIAL HYPOXIA

遗传学与间歇性心肌缺氧

• 批准号: 6527701
• 负责人: JOHN E BAKER
• 金额: $ 26.16万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6527701
• 关键词: gene expression; genetic mapping; genetic susceptibility; laboratory rat; microarray technology; myocardial ischemia /hypoxia; phenotype; quantitative trait loci

The overall objective is to localize the gene(s) responsible for susceptibility to myocardial ischemia caused by intermittent hypoxia and characterize the physiology in a novel model system. Patients with obstructive sleep apnea have an increased cardiovascular morbidity and mortality. Diseases such as hypertension, hyperlipidemia and diabetes mellitus have an underlying genetic basis and represent risk factors for ischemic heart disease. However, the genetic components(s) underlying the impact of intermittent hypoxia on susceptibility to myocardial ischemia are unknown. It is hypothesized that genetic factors are responsible for increased susceptibility to myocardial ischemia caused by intermittent hypoxia in Dahl S rats compared with Brown Norway rats. This hypothesis will be tested by crossing the Brown Norway with Dahl S rat. The isolated heart model and coronary vessels will be used to facilitate discrete, well-controlled investigations of susceptibility to ischemia with and without prior intermittent hypoxia. A total genome scan will be performed to map quantitative trait loci (QTLs) involved in adaption to intermittent hypoxia and susceptibility to myocardial ischemia. Phenotypic difference between parents and the congenic derivatives resulting form ischemia and reperfusion will be characterized. The specific aims are to: 1) Determine the phenotypic differences of isolated hearts and coronary vessels from the parental strains by studying the responses to: ischemia alone and adaptation to intermittent hypoxia prior to ischemia; 2) Map the gene(s) responsible for adaption in intermittent hypoxia and susceptibility to myocardial ischemia using a total genome scan approach; 3) Develop congenic strains in response to: ischemia alone and adaptation to intermittent hypoxia prior to ischemia; and 4) Use microarray technology to study the expression of genes within the heart adapted to intermittent hypoxia. This project may provide detailed information regarding the genetic basis for adaption to intermittent hypoxia and susceptibility to myocardial ischemia in a genetic model system, which may prove useful for detailed physiological, biochemical and pharmacological assessment.

总体目标是定位负责的基因 间歇性缺氧引起的心肌缺血易感性 在新颖的模型系统中表征生理学。 患者患有 阻塞性睡眠呼吸暂停会增加心血管疾病的发病率 死亡。 高血压、高血脂、糖尿病等疾病 mellitus 具有潜在的遗传基础并代表了危险因素 缺血性心脏病。 然而，潜在的遗传成分 间歇性缺氧对心肌缺血易感性的影响 未知。 据推测，遗传因素是导致 间歇性缺氧导致心肌缺血的易感性增加 达尔 S 大鼠与棕色挪威大鼠进行比较。 这个假设将是 通过与 Dahl S 大鼠穿越布朗挪威进行测试。 离体心脏模型 冠状血管将用于促进离散的、良好控制的 有或没有事先进行缺血易感性的调查 间歇性缺氧。 将进行全基因组扫描以绘制图谱 参与适应间歇性缺氧的数量性状位点（QTL） 以及心肌缺血的易感性。 之间的表型差异 亲本以及由缺血和再灌注引起的同源衍生物 将被表征。 具体目标是： 1) 确定表型 离体心脏和冠状血管与亲本品系的差异 通过研究以下反应： 单独缺血和适应间歇性 缺血前缺氧； 2）绘制负责适应的基因 间歇性缺氧和对心肌缺​​血的易感性 基因组扫描方法； 3) 开发同源菌株以应对：缺血 单独适应缺血前的间歇性缺氧； 4) 使用 微阵列技术研究心脏内基因的表达 适应间歇性缺氧。 该项目可能会提供详细的 有关适应间歇性缺氧的遗传基础的信息 以及遗传模型系统中对心肌缺血的易感性，这可能 证明对详细的生理、生化和药理学有用 评估。