Genetic and Cellular Basis of Resistance/Sensitivity to Myocardial Ischemia

对心肌缺血的抵抗/敏感性的遗传和细胞基础

• 批准号: 8118273
• 负责人: HOWARD J JACOB
• 金额: $ 58.33万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8118273
• 关键词: Animal Model; Animals; Blood Platelets; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cessation of life; Characteristics; Chromosomes; Chromosomes, Human, Pair 3; Chromosomes, Human, Pair 6; Communities; Complex; Coronary Arteriosclerosis; Developing Countries; Engineering; Ensure; Future; Genes; Genetic; Genetic Models; Genetic Polymorphism; Genomics; Goals; Gold; Grant; Haplotypes; Health; Heart; Heterogeneity; Human; In Vitro; Inbred Strains Rats; Injury; Ischemia; Knowledge; Lead; Leptin; Link; Maps; Morbidity - disease rate; Mutation; Myocardial Infarction; Myocardial Ischemia; Myocardium; Nature; Norway; Obesity; Outcome; Pathway interactions; Patients; Phenotype; Physiological; Play; Predisposition; Process; Property; Quality of life; Rattus; Recovery; Reperfusion Therapy; Research; Resistance; Risk; Role; Severities; Signal Pathway; Solutions; Study models; Testing; Time; Tissue Model; Tissues; Transgenic Animals; Transgenic Organisms; United States; Validation; Western World; base; congenic; consomic; density; experience; genetic linkage analysis; genome wide association study; innovation; insight; mortality; new technology; positional cloning; premature; prevent; programs; public health relevance; research study; response; salt sensitive; success; therapy development; tool; trait

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.

描述（由申请人提供）：心肌梗塞（MI）是美国的主要健康问题。心脏对缺血的抗药性和/或敏感性的多基因性质被广泛接受。人类研究和动物模型中的基因组广泛的研究和联系分析表明，大量染色体基因座参与冠状动脉疾病（CAD）和MI。不幸的是，在确定与缺血性损伤的反应直接相关的因果多态性方面，几乎没有取得进展。与人类研究相反，动物模型提供了通过使用特定的遗传模型与发散表型来识别复杂相互作用的能力，例如敏感的Dahl盐敏感和抗性的棕色挪威菌株。为了剖析这种复杂性，我们提出：1。识别负责缺血性抗性的大鼠染色体上的基因。我们将将最初的位置克隆工作重点放在S.BN6最小的含有36个基因的3.9mb的先天性上。这个目标的意义在于，我们很可能在此间隔中识别和验证因果突变。使用工程心组织（EHT）加速发现并增强我们研究突变的机械性能的能力是创新的。 2.追求负责对大鼠染色体3和12缺血的基因的识别。使用SS.BN3和SS.BN12修复学，我们已经产生了友善，并证明我们可以使用我们的体外（Langendorff）和EHT模型在这两个染色体上进行探索。此外，利用另外两种菌株/染色体将使心肌缺血的复杂性更好地理解。 3.负责缺血性抗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救援实验。我们将采用转基因救援方法来验证6号染色体基因座。该目标的重要性是证明突变是随意的，并使用创新的解决方案来产生转基因救援动物。最后，将向研究界提供动物模型以进行进一步研究。 公共卫生相关性：心血管疾病是全世界死亡的主要原因之一，是西方世界中45％的死亡，而发展中国家的死亡人数为24.5％。尽管抗动脉粥样硬化疗法，再灌注策略和抗血域疗法，心肌梗死仍然是发病率和死亡率的主要原因，这部分是由于患者缺血的反应中存在较大的异质性。该项目的总体目标是识别涉及对心肌梗塞抗性的基因和机制。