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.

总体目的是定位负责的基因 由间歇性缺氧引起的心肌缺血的敏感性 在新型模型系统中表征生理学。 患者 阻塞性睡眠呼吸暂停的心血管发病率增加 死亡。 高血压，高脂血症和糖尿病等疾病 Mellitus具有潜在的遗传基础，并代表了风险因素 缺血性心脏病。 但是，遗传成分（s） 间歇性缺氧对心肌缺血易感性的影响是 未知。 假设遗传因素是造成的 间歇性缺氧引起的心肌缺血的敏感性增加 与棕色挪威大鼠相比，在达尔的大鼠中。 这个假设将是 通过将挪威与达尔的大鼠越过棕色挪威测试。 孤立的心脏模型 和冠状血管将用于促进离散，控制良好 对缺血的易感性调查有或没有先验 间歇性缺氧。 将进行总基因组扫描以映射 与间歇性缺氧适应的定量性状基因座（QTL） 以及对心肌缺血的敏感性。 表型之间的差异 父母和先天衍生物产生的缺血和再灌注 将被描述。 具体目的是：1）确定表型 父母菌株中孤立的心脏和冠状动脉血管的差异 通过研究：单独缺血的反应并适应间歇性 缺血之前缺氧； 2）映射负责适应的基因 间歇性缺氧和对心肌缺​​血的敏感性使用总计 基因组扫描方法； 3）响应以下疾病，发展出良性菌株：缺血 缺血之前单独适应间歇性缺氧； 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 在遗传模型系统中对心肌缺血的敏感性，这可能 被证明可用于详细的生理，生化和药理学 评估。