Rapamycin引起雄性不育和mTOR信号通路调控精子发生的分子机制研究

雷帕霉素(rapamycin)是哺乳动物雷帕霉素靶蛋白(mTOR)的抑制剂, 它抑制细胞增殖，增强干细胞的自我更新功能，促进细胞自噬和延长小鼠的寿命。目前rapamycin和它的类似物rapalogs广泛用于器官移植和癌症治疗，但临床上接受rapamycin作为免疫抑制剂的男性病人中，出现了不育的症状。mTOR是一类丝氨酸/苏氨酸蛋白激酶,在体内形成mTORC1和mTORC2两种不同复合体。mTORC1复合体通过S6K1和4E-BP1调控核糖体的生物合成和蛋白翻译；mTORC2复合体通过AKT, SGK和PKCα调控血糖代谢和细胞骨架。我们将通过分析rapamycin处理小鼠的生殖表型，利用睾丸生殖细胞特异性Raptor(mTORC1)或Rictor(mTORC2)敲除小鼠，深入阐述rapamycin引起雄性不育的分子机制，为设计和开发新一代特异性的rapalogs提供理论基础。

Rapamycin is an inhibitor of the mTOR(mammalian Target of Rapamycin),it suppresses cell proliferation,promotes stem cell self-renewal capacity,regulates autophagy and extends lifespan in mice. Rapamycin and its analogs(rapalogs) are now FDA approved as immunosuppressants and anticancer agents which are widely used in organ transplanted and cancer patients. However,there are many reports regarding rapamycin's undesirable side effects, one of which is the reduced fertility observed in male kidney transplanted recipients. mTOR is an serine/threonine protein kinase, which forms two large distinct complexes mTORC1 and mTORC2 through interacting with different proteins.mTORC1 regulates ribosome biogenesis and protein translation via phosphorating downstream targets including S6 kinase1(S6K1) and eukaryotic translation initiation factor 4E-binding protein(4E-BP1).mTORC2 plays an essential role in glucose metabolism and the cytoskeleton through AKT,serum/glucocorticoid induced kinase(SGK) and protein kinase C(PKC-α).Our study will systemically uncover changes in mTOR signaling pathway and spermatogenesis in rapamycin treated mice, and reveal the underlying mechanism accounting for infertility in rapamycin treated mice. This study will provide fundamental basis for designing next generation of rapalogs.