USP42在精子发生过程中的功能研究及机制探讨

The ubiquitin-proteasome pathway is an important protein degradation regulation system, participating in the regulation of cell proliferation, differentiation and apoptosis.The pathway plays an important role in the reproductive system.The deubiquitinating enzymes (DUBs)has been involved in regulation of this system which maintain free ubiquitin in cells and regulate downstream substrates. DUBs had been reported that play an important role in spermatogenesis, but the mechanism is unclear.Based on our mouse testis protiomics and the information of knockout mice announced from EUCOMM company, we selected the USP42 protein to study.Our previous studies have confirmed that USP42 protein expressed highly in mouse testis, and specific localized in sertoli cells in the seminiferous epithelium.Our male knockout mice also showed infertility.Here we will use the knockout mice as a research models , analyze the infertility of male mice to reveal role of USP42 in the testis, and further screening downstream substrate, and the interacted proteins, explore its mechanism. In addition, we will combine the clinical cases, analysis of the correlation between of USP42 gene mutations and male infertility, supporting the evidences and targets for the diagnosis and therapy on infertility patients.

泛素-蛋白酶体途径是细胞内一个重要的蛋白质降解调节系统，参与和调控细胞的增殖、分化和凋亡，在生殖系统中起着重要调控作用。去泛素化酶是参与调控这一系统的重要蛋白，其维持细胞内游离泛素的稳态并调节下游底物蛋白的水平和功能。已有的相关报道提示去泛素化酶对精子发生起着重要作用，但作用机制尚不明确。我们结合实验室构建的小鼠睾丸蛋白谱系及EUCOMM公司公布的敲除小鼠信息，挑选了USP42蛋白这个去泛素化酶家族成员进行研究。我们的前期结果已经证实USP42蛋白在小鼠睾丸中优势表达，并在生精上皮中特异定位于支持细胞，雄性敲除小鼠也呈现生殖力障碍，本研究将以敲除小鼠为研究模型，通过深入分析敲除小鼠的生殖功能缺陷，揭示USP42在睾丸中的作用，并进一步寻找下游底物及相互作用分子，深入探讨其作用机制。此外，我们将结合临床病例，分析USP42基因突变与男性不育之间的相关性，为不育患者提供诊断依据和治疗靶标。