Genetic and Cellular Basis of Resistance/Sensitivity to Myocardial Ischemia

描述（由申请人提供）：心肌梗死（MI）是美国的一个主要健康问题。心脏对缺血的抗性和/或敏感性的多基因性质是公认的。在人类研究和动物模型中的全基因组关联研究和连锁分析揭示了大量涉及冠状动脉疾病（CAD）和MI的染色体位点。不幸的是，在确定与缺血性损伤反应直接相关的因果多态性方面几乎没有进展。与人类研究相反，动物模型提供了通过使用具有心肌缺血的不同表型的特定遗传模型（例如敏感的Dahl盐敏感性和耐药性Brown Norway菌株）来鉴定复杂相互作用的能力。为了相应地剖析这种复杂性，我们提出：1。确定大鼠6号染色体上负责抵抗缺血的基因。我们将把我们最初的定位克隆工作集中在SS. BN 6最小同源，包含3.9Mb，含有36个基因。这一目标的意义在于，我们很有可能在这一区间内识别和验证因果突变。使用工程心脏组织（EHT）来加速发现并提高我们研究突变的机械特性的能力是创新的。2.在大鼠3号和12号染色体上寻找负责抗缺血的基因。使用SS.BN3和SS.BN12同源体，我们已经产生了同源体，并证明我们可以使用我们的体外（Langendorff）和EHT模型来追踪这两条染色体上的基因座。此外，利用另外两个菌株/染色体将导致更好地理解心肌缺血的复杂性。3.负责抗缺血性的基因的功能验证。证明基因是因果关系的黄金标准需要某种形式的拯救实验。我们将部署一种转基因拯救方法来验证6号染色体位点。这一目标的意义在于证明突变是偶然的，并使用创新的解决方案来产生转基因救援动物。最后，动物模型将提供给研究界进行进一步研究。 公共卫生相关性：心血管疾病是世界范围内死亡的主要原因之一，在西方世界占死亡人数的45%，在发展中国家占死亡人数的24.5%。尽管有抗动脉粥样硬化治疗、再灌注策略和抗血小板治疗，心肌梗死仍然是发病率和死亡率的主要原因，部分原因是患者对缺血的反应具有很大的异质性。该项目的总体目标是确定参与抵抗心肌梗死的基因和机制。

DESCRIPTION (provided by applicant): Myocardial infarction (MI) is a major health problem in the United States. The polygenic nature of the resistance and/or sensitivity of the heart to ischemia are well accepted. Genome wide association studies and linkage analyses in both human studies and animal models have revealed a large number of chromosomal loci involved in coronary artery diseases (CAD) and MI. Unfortunately, little progress has been made in identifying causal polymorphisms directly related to the response to ischemic injury. In contrast to human studies, animal models provide the ability to identify the complex interactions through the use of specific genetic models with divergent phenotypes for myocardial ischemia such as the sensitive Dahl Salt-Sensitive and resistant Brown Norway strains. To dissect this complexity accordingly we propose: 1. Identify a gene on rat chromosome 6 responsible for resistance to ischemia. We will focus our initial positional cloning efforts on the SS.BN6 minimal congenic encompassing 3.9Mb containing 36 genes. The significance of this aim is that we are very likely to identify and validate the causal mutation in this interval. The use of engineered heart tissue (EHT) to accelerate discovery and enhancing our ability to study the mechanistic properties of the mutation is innovative. 2. Pursue the identification of the genes responsible for resistance to ischemia on rat chromosomes 3 and 12. Using SS.BN3 and SS.BN12 consomics we have already generated congenics and demonstrated that we can use our in vitro (Langendorff) and EHT models to pursue loci on these two chromosomes. Moreover, utilizing another two strains/chromosomes will lead to better understanding complexity of myocardial ischemia. 3. Functional validation of the gene(s) responsible for the resistance to ischemia. The gold standard for proving that a gene is causal requires some form of rescue experiment. We will deploy a transgenic rescue approach to validate the chromosome 6 locus. The significance of this aim is proving a mutation is casual and uses innovative solutions to generate the transgenic rescue animals. Finally, the animal models will be made available to the research community for further studies. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is one of the leading causes of death worldwide and is responsible for 45% of deaths in the Western world and 24.5% of deaths in the developing countries. Myocardial infarction remains a major cause of morbidity and mortality despite anti-atherosclerotic therapies, reperfusion strategies, and anti-platelet treatment, due in part to the large heterogeneity in the response to ischemia among patients. The overall goal of this project is to identify genes and mechanisms involved in resistance to myocardial infarction.