PAQR7在精子响应孕酮能力下降的男性不育症中的作用机制

Progesterone plays an important role in the regulation of sperm function. In some infertile males, the ability of sperm responding to progesterone is significantly reduced, but the underlying molecular mechanisms are unknown. The previously published results indicated that sperm specific calcium channel, CatSper, is closely related to the responsiveness of sperm to progesterone. Our latest results showed that progestin–adiponectin Q receptor 7 (PAQR7) interacts with CatSper and PAQR7 monoclonal antibody significantly inhibited the ability of sperm responding to progesterone. More importantly, 55% male infertile patients whose sperm show decreased calcium responsiveness to progesterone have reduced PAQR7 content in their sperm. Therefore, we hypothesized that decreased PAQR7 content plays an important role in the male infertile patients whose sperm show decreased responsiveness to progesterone. With the stochastic optical reconstruction microscopy, calcium signal measurement, sperm patch clamp and other means, the project intends to: 1) clarify the relationship between decreased PAQR7 content and male infertility by large sample screening; 2) reveal the effects of decreased PAQR7 content on sperm intracellular signal pathways such as CatSper/Ca2+ dependent pathway; 3) elucidate the function mechanisms underlying decreased PAQR7 content in the male infertile patients whose sperm show decreased responsiveness to progesterone. This topic is expected to find a new pathogenic factor of male infertility, so as to provide a candidate target for accurate diagnosis and treatment of male infertility.

孕酮是调控精子功能的重要生理因子，部分男性不育症患者精子响应孕酮能力显著降低，但相关分子机制不明。前人和申请人已发表的结果表明精子响应孕酮与精子特异性钙通道CatSper密切相关；且申请人最新结果显示：孕酮脂联素受体7（PAQR7）是CatSper的互作蛋白，其单克隆抗体显著抑制精子响应孕酮的能力；更重要的是55%孕酮钙响应下降的男性不育症患者精子中PAQR7含量降低。据此，我们假设PAQR7含量降低在精子响应孕酮能力下降类男性不育症中扮演重要角色。结合超高分辨显微技术、钙信号测量、精子膜片钳等手段，本项目拟：1）大样本下阐明PAQR7含量降低与男性不育症的内在联系；2）揭示PAQR7含量降低对精子CatSper/Ca2+等孕酮相关胞内信号途径的影响；3）探明PAQR7含量降低在精子响应孕酮能力下降类男性不育症中的功能机制。本课题有望发现男性不育新的致病因子，从而为其精准诊疗提供候选靶标。

孕酮是调控精子功能的重要生理因子，部分男性不育症患者精子响应孕酮能力显著降低，但相关分子机制不明。前人和申请人已发表的结果表明精子响应孕酮与精子特异性钙通道CatSper密切相关；此外，孕酮脂联素受体7（PAQR7）是CatSper的互作蛋白，其单克隆抗体显著抑制精子响应孕酮的能力；更重要的是55%孕酮钙响应下降的男性不育症患者精子中PAQR7含量降低。这些结果都暗示，PAQR7含量降低在精子响应孕酮能力下降的男性不育症中扮演重要角色。本项目结合超高分辨显微技术、钙信号测量、精子膜片钳等手段，在大样本下筛查了PAQR7含量降低与孕酮增加精子胞内钙以及精子前向运动的相关性，研究了PAQR7含量降低对精子CatSper/Ca2+和cAMP介导的精子胞内信号通路的影响，并探讨了PAQR7含量降低在特发性男性不育症中的功能机制。结果表明，1）PAQR7含量降低与孕酮响应精子能力减弱的男性不育症以及特发性弱精子症密切相关。2）PAQR7与孕酮响应关键蛋白ABHD2相互作用，且细胞中PAQR7含量降低会削弱孕酮激活ABHD2水解抑制CatSper钙通道活性的2-AG的能力，故而孕酮增加CatSper电流效应减弱、提升胞内钙浓度能力降低，对精子穿粘液和顶体反应激活下降，从而影响精子响应孕酮和受精能力，导致男性不育症。 3）PAQR7含量降低会减少精子中cAMP含量，抑制PKA活性，这可能是PAQR7含量降低导致弱精子症的证据之一。本项目的结果不仅补充和完善了倍受关注的孕酮-CatSper作用理论，而且为揭示特发性男性不育症的发病机制提供了理论基础，有望为特发性男性不育症的诊疗以及男性生殖调控药物的开发提供新的分子靶标。