Genetic and Cellular Basis of Resistance/Sensitivity to Myocardial Ischemia

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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.