DNA损伤修复蛋白BRCA1维持未分化精原细胞稳态的机制研究

未分化精原细胞是男性出生后精子发生的起始，长期维持未分化精原细胞的稳态是保持成年男性数十年生育力的决定因素。目前我们对未分化精原细胞的稳态维持调控的认识主要停留在基因转录与蛋白翻译水平，对其他信号通路是否参与调控尚不清楚。BRCA1是一个重要的DNA损伤修复蛋白，我们的前期工作发现BRCA1生殖细胞特异敲除雄性小鼠中未分化精原细胞的稳态维持出现障碍，导致未分化精原细胞提早耗竭，提示BRCA1可能参与调控未分化精原细胞的稳态维持以防止生殖早衰。本项目将系统研究BRCA1缺失后未分化精原细胞的命运改变，并研究BRCA1缺失导致未分化精原细胞稳态破坏的原因，力争阐明BRCA1在未分化精原细胞中通过DNA损伤修复维持未分化精原细胞稳态的分子机制。本项目的研究结果将深化我们对未分化精原细胞的稳态维持调控的认识，并对男性生殖早衰与男性不育的病因诊断有着指导意义。

Spermatogenesis can continuously occur in adult male for decades, owing to long-term homeostatic maintenance of undifferentiated spermatogonia. Our current understanding of how this process is regulated remains at the level of gene transcription and protein translation. It is still elusive if other signaling pathways are also involved. Interestingly, male germ cell-specific knockout mice of BRCA1, an important protein in DNA damage repair, fail to maintain homeostasis of undifferentiated spermatogonia and have accelerated depletion of these cells. This observation suggests that BRCA1 could be a new player in regulation of homeostasis of undifferentiated spermatogonia. In this proposal, we plan to systematically examine the fate of undifferentiated spermatogonia after BRCA1 depletion and the reasons underlying the disruption of homeostasis of undifferentiated spermatogonia. We will strive to reveal the mechanistic role of BRCA1-dependent DNA damage repair in maintaining homeostasis of undifferentiated spermatogonia as well. Our finding will not only extend our knowledge about homeostatic regulation of undifferentiated spermatogonia, but also shed light on the diagnosis for premature aging of male germ cells and male infertility.