Mapping Murine Regeneation Genes

描述（由申请人提供）：伤口和组织损伤是常见的医学问题，通常会导致过度的疤痕形成和随后的器官功能丧失，而没有正常的组织替代。了解控制无疤痕再生愈合的分子可以为调节愈合和减轻这些对公众健康的重大威胁提供一种手段。我们之前已经证明，成年MRL小鼠显示出独特的无疤痕和再生型愈合。在这些小鼠中，贯穿耳孔的伤口完全愈合，而其他小鼠的耳孔则会留下疤痕。MRL小鼠耳部伤口显示软骨和毛囊再生。此外，在心脏右心室冷冻损伤后，我们已经显示愈合发生无疤痕，心肌细胞几乎完全替代，并恢复正常功能。我们还证明了耳孔闭合表型受多个遗传位点控制，是一种复杂的数量性状，并受性别的深刻影响。基于这些观察结果，我们建议结合连锁定位和基因表达谱来识别调节小鼠再生愈合的基因。近亲繁殖的MRL小鼠株来自LG小鼠株，LG小鼠株是唯一显示出具有这种再生能力的菌株。构建了LG/J（大）和SM/J（小）小鼠之间的高级杂交系（AIL）和大型重组近交系（Rl），为我们提供了独特的方法来研究它们的再生愈合，探索它们的全范围表型，并绘制这些MRL祖细胞中的再生基因。在这项提议中，一个由四个实验室组成的联盟将进行表型分型、基因分型、基因表达研究和体外伤口愈合试验。具体目标是：1。产生500只LGXSM F2小鼠进行初始QTL定位，1000只LGXSM AIL小鼠进行精细定位；2. 用成纤维细胞、内皮细胞和角化细胞对耳孔闭合进行亚表型分析并分析体外伤口愈合；3. 通过比较显示不同愈合特性的细胞和耳组织来研究基因表达。虽然这些具体目标是协同的，但它们可以独立完成，以提供有意义的信息。我们利用定义良好的LGXSM小鼠资源对再生愈合进行研究，使我们认识到这种基因强大且独特的愈合模型系统的巨大潜力。

DESCRIPTION (provided by applicant): Wound and tissue injuries are common medical problems that often lead to excessive scar formation and subsequent loss of organ function without normal tissue replacement. Understanding the molecules that control scarless regenerative healing can provide a means to modulate healing and mitigate these significant threats to public health. We have demonstrated previously that adult MRL mice show unique scarless and regenerative-type healing. In these mice, through-and-through ear hole wounds close completely, whereas those in other mice scar. Ear wounds of MRL mice display re-growth of cartilage and hair follicles. In addition, following cryoinjury to the right ventricle of the heart, we have shown healing occurs without scarring, with nearly complete replacement of cardiomyocytes, and with return to normal function. We have also demonstrated that the ear hole closure phenotype is controlled by multiple genetic loci, is a complex quantitative trait, and is profoundly influenced by sex. Based on these observations, we propose to identify the genes that regulate regenerative healing in mice using a combination of linkage mapping and gene expression profiling. The inbred MRL mouse strain derives from the LG mouse strain, which is the only other strain shown to have this regenerative capacity. An advanced intercross line (AIL) and a large panel of recombinant inbred (Rl) strains between LG/J (Large) and SM/J (Small) mice has been constructed that provides us the unique means to examine their regenerative healing, to explore the full range of their phenotypes, and to map the regeneration genes in these MRL progenitors. In this proposal, a consortium of four, laboratories will carry out phenotyping, genotyping, gene expression studies, and in vitro wound healing assays. The specific aims are: 1. Generating 500 LGXSM F2 mice for initial QTL mapping and 1000 LGXSM AIL for fine mapping; 2. Sub-phenotyping ear hole closure and analyzing in vitro wound healing using fibroblasts, endothelial cells, and keratinocytes; 3. Studying gene expression by comparing cells and ear tissue that display differential healing properties. Although synergistic, these specific aims can be accomplished independently of each other to provide significant information. Our study of regenerative healing using the well-defined LGXSM mouse resource enables us to realize the promising potential of this genetically powerful and unique healing model system.