下丘脑-垂体-睾丸轴对间质干细胞的调节以及其异常导致性功能低下的机制研究

睾丸间质干细胞（LSC）自我更新和分化受到下丘脑-垂体-睾丸轴和微环境产生的信号分子调控。前期实验发现LSC有向Leydig和Myoid细胞双向分化的潜能以及NGF和IGF-1在多水平参与调控。目前许多关键基因调控的机制仍不清楚。我们提出假说：下丘脑-垂体-Sertoli细胞轴分泌介导SF1转录的DHH是LSC向Leydig细胞分化的关键因子，而PDGFBB介导MyoD转录是LSC向Myoid细胞分化的核心调控通路。拟采用小鼠细胞特异性基因敲除或过表达及细胞实时成像跟踪研究：①LSC特征是什么？②PDGF和受体在调节LSC的作用和机制；③DHH在LSC定向分化的作用和机制；④WNT信号与黄体生成素互作在调控LSC自我更新和分化的机制；⑤NGF-IGF-1在下丘脑-垂体-睾丸轴调控LSC自我更新和分化的机制。这些研究将为解决干细胞治疗性功能低下提供基础。

Leydig stem cells (LSC) can self-renew and differentiate and these are regulated by signal molecules produced by the hypothalamic-pituitary-testicular axis and niche. Pilot studies have shown that LSC is the multipotent stem cell, having potential to differentiate into either Leydig or myoid cell, and that NGF and IGF-1 are involved in regulation of these processes at multiple levels. At present, many of the mechanisms of key gene regulation are still unclear. We hypothesized that DHH , regulated by hypothalamic-pituitary-Sertoli cell axis, is a key factor in the differentiation of LSC into the Leydig cell lineage whereas PDGFBB mediates MyoD transcription as the core regulatory pathway for LSC into the myoid cell lineage. Using gene conditional knockout or overexpression and cell real-time imaging tracking study, we will study: ① what is the characteristics of LSC? ②the mechanism and PDGF and its receptor in regulating LSC; ③the mechanism of DHH in regulating LSC; ④the mechanism of WNT signal interacting with luteinizing hormone in regulating LSC self-renewal and differentiation; ⑤the mechanism of NGF/IGF-1 in the hypothalamus-pituitary-testicular axis in regulating LSC. These studies will provide a basis for addressing the therapeutic efficacy of stem cells.