Genetic Determinants of Adult Mouse Heart Regeneration

 描述(申请人提供)：心脏病发作导致心肌细胞(CMS)死亡。大多数成年哺乳动物的CMS是有丝分裂后的，这有效地阻止了损伤后的再生和功能恢复。最近的研究表明，成年哺乳动物确实存在CM细胞分裂，尽管程度非常有限；这意味着存在 具有启动细胞分裂和实现某种程度再生的能力的CMS的一小部分。不幸的是，大多数人发生这种情况的程度太小，不能恢复正常的心脏功能，因此心力衰竭仍然是主要的死亡原因。 在西方世界。强有力的证据支持这一模型，即单核、二倍体CMS是成年哺乳动物心脏中相对罕见的种群，是具有再生能力的种群。这个项目探索了这样一种假设，即成年哺乳动物心脏中这些单核、二倍体CMS的频率和再生潜力是由多个遗传参数决定的两个相互关联的变量性状。如果是这样的话，基于他们独特的遗传背景，不同的个体在受伤后进行心脏再生的能力将会更大或更小。对小鼠的初步研究表明，不同近交系之间单核、二倍体CMS的数量有很大差异，这与DNA分裂的频率和损伤后心功能的改善有关。这一模型的一个扩展是，关联研究可以确定导致这种观察到的变异的遗传基因。杂交小鼠多样性小组是一组近亲交配的小鼠品系，旨在加快这一类型的遗传关联研究，将用于识别与单核、二倍体CMS频率相关的基因。到目前为止，位于3号染色体上的两个基因座已经上升到有关联研究的意义。这项建议将验证候选基因(S) 存在最优先的基因座，因为它们在维持单核、二倍体种群b方面发挥了作用，在小鼠模型中对基因的表达进行了遗传操纵，并量化了这种遗传操纵对种群的影响。第二个实验将评估经过验证的基因(S)以及群体对心脏损伤后再生能力的影响，从而明确地将单核、二倍体CM群体与心脏再生联系起来。

 DESCRIPTION (provided by applicant): A heart attack results in the death of cardiomyocytes (CMs). Most adult mammalian CMs are post-mitotic, which effectively prevents regeneration and restoration of function following damage. Recent studies have demonstrated that CM cell division does occur in adult mammals, albeit to a highly limited extent; this implies the existence of a small subset of CMs that has the capacity to initiate cell division and achieve some measure of regeneration. Unfortunately, the extent to which this occurs in most people is too little to restore normal heart function, such that heart failure remains the leading cause of death in the Western world. Strong evidence supports the model that mononuclear, diploid CMs, a relatively rare population in the adult mammalian heart, are a regeneration-competent population. This project explores the hypothesis that the frequency of these mononuclear, diploid CMs in the adult mammalian heart and regenerative potential are two interlinked variable traits determined by multiple genetic parameters. If so, different individuals will have a greater r lesser capacity to undergo heart regeneration following injury, based on their unique genetic backgrounds. Preliminary studies in mice demonstrate a substantial variation in the number of mononuclear, diploid CMs across different inbred strains and this correlates with both frequency of DNA division and improved cardiac function following injury. An extension of this model is that association studies could identify the genetic loci responsible for this observed variation. The Hybrid Mouse Diversity Panel, a collection of inbred mouse strains designed to expedite genetic association studies of this type, will be used to identify the genes correlated with the frequency of mononuclear, diploid CMs. So far, two loci located on chromosome 3 have already risen to significance with association studies. This proposal will validate the candidate gene(s) within the existing highest priority locus for their role in maintaining the mononuclear, diploid population b genetically manipulating the expression of the gene in a mouse model and quantifying the effect of that genetic manipulation on the population. A second experiment will assess the effect the validated gene(s), and therefore the population, have on the ability of the heart to regenerate after injury, thereby definitively link the mononuclear, diploid CM population to heart regeneration.