Genetic Determinants of Adult Mouse Heart Regeneration

 描述（由申请人提供）：心脏病发作导致心肌细胞（CM）死亡。大多数成年哺乳动物CM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，CM细胞分裂确实发生在成年哺乳动物中，尽管程度非常有限;这意味着CM细胞分裂的存在。 有能力启动细胞分裂并实现某种程度的再生的CM的一个小子集。不幸的是，大多数人发生这种情况的程度太小，无法恢复正常的心脏功能，因此心力衰竭仍然是死亡的主要原因 在西方世界。强有力的证据支持的模型，单核细胞，二倍体CM，一个相对罕见的人口在成年哺乳动物的心脏，是一个再生能力的人口。该项目探讨了这样一种假设，即这些单核、二倍体CM在成年哺乳动物心脏中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可变性状。如果是这样的话，不同的个体将有更大或更小的能力，在受伤后进行心脏再生，基于他们独特的遗传背景。在小鼠中的初步研究表明，在不同的近交系中，单核、二倍体CM的数量存在显著差异，这与DNA分裂频率和损伤后心脏功能的改善相关。该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位点。杂交小鼠多样性小组，一个旨在加快这种类型的遗传关联研究的近交系小鼠品系的集合，将用于鉴定与单核细胞、二倍体CM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在关联研究中发挥了重要作用。该提案将验证候选基因中的 现有的最高优先级基因座在维持单核二倍体群体B中的作用，b.在小鼠模型中遗传操作基因的表达，并量化遗传操作对群体的影响。第二个实验将评估经验证的基因以及群体对损伤后心脏再生能力的影响，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.