灵长类睾丸特异蛋白TDRG1介导弱精子症的钙信号机制研究

Asthenospermia, a common disease of male infertility, which pathogenesis is unknown. It may be related to abnormal expression of testicular specific gene. The testicular development related gene 1 (TDRG1) is a specific gene of the primate testis that the applicant participates in identification.The latest experimental results show that the content of TDRG1 was linearly correlated with sperm motility; cell penetrating peptide TAT can carry TDRG1 into mature sperm and significantly improve the progressive spermatozoa of asthenospermia (increased by 40%); More importantly, the content of CATSPER1 decreased while the TDRG1 content decreased in the spermatozoa of asthenospermia, and there was interaction between CATSPER1 and TDRG1. Accordingly, we hypothesized that TDRG1 regulates the motility of human sperm through the interaction of CATSPER and its abnormality leading to asthenospermia. With the stochastic optical reconstruction microscopy, calcium signal measurement, sperm patch clamp and other means, the project intends to: 1) clarify the internal relationship between TDRG1 and CATSPER1; 2) reveal the effects of TDRG1 on sperm intracellular signal pathways regulating human sperm motility; 3) explore the functional mechanism of TDRG1 in male infertility. This paper is expected to find new pathogenic factors of weak sperm disease, so as to provide a candidate target for accurate diagnosis and treatment.

弱精子症是男性不育常见病症且发病机制不明，可能与睾丸特异性基因表达异常有关。睾丸发育相关基因1（TDRG1)是申请人参与鉴定的灵长类睾丸特异性基因。申请人最新实验结果显示：TDRG1含量与精子活力呈正相关；穿膜肽TAT能将TDRG1导入人成熟精子并显著改善弱精子症精子的前向运动（提高约40%）；更重要的是弱精子症精子中TDRG1含量下降的同时精子特异性钙通道CATSPER1含量也下降，且CATSPER1与TDRG1相互作用。据此，我们假设：TDRG1通过CATSPER相互作用调控人精子运动、其异常导致弱精子症。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）阐明TDRG1与CATSPER1的相互作用关系；2）揭示TDRG1调控人精子运动的胞内钙信号相关途径；3）探讨TDRG1在男性不育症中的功能机制。本课题有望发现弱精子症新的致病因子，从而为其精准诊断与治疗提供候选靶标。

弱精子症是男性不育常见病症且发病机制不明，可能与睾丸特异性基因表达异常有关。睾丸发育相关基因1（TDRG1)是申请人参与鉴定的灵长类睾丸特异性基因。申请人已证实：1）TDRG1含量与精子活力呈正相关；2）穿膜肽TAT能将TDRG1导入人成熟精子并显著改善弱精子症精子的前向运动（提高约40%）；3）CATSPER1与TDRG1相互作用，即TDRG1是弱精子症新的致病因子，上述研究成果已发表在生殖领域TOP期刊Human Reproduction, 2021, 36(2)：283，获得国家发明专利 1项（一种用于诊断弱精子症的生物标记物，ZL.2019 1 0546487.6.）和省自然科学奖1项。我们采用结合超高分辨显微技术、钙信号测量、精子膜片钳等手段初步阐明了TDRG1调控人精子运动的胞内钙信号相关途径进而探讨了TDRG1在男性不育症中的功能机制，从而为其精准诊断与治疗提供候选靶标。