E3泛素连接酶TRIM69在睾丸抗病毒天然免疫调节中的功能

Infectious and inflammatory conditions in the reproductive system are among etiological factors of male infertile. Testis, a typical immune exemption organ, is susceptible to infection of various pathogens, especially virus infection. For the defense against pathogen infection, the testis has established a local innate immune defense mechanism. It is of great significance to clarify the innate immune defense mechanism of testicles for the prevention and treatment of infectious infertility. TRIM family proteins are widely involved in innate immune response and regulation. TRIM69 is a new member of TRIM family, its function in immune regulation has not been investigated. Previous study found that TRIM69 is specifically expressed in the testis. Trim69 can inhibit the TLR signaling pathway gene expression, interact with NF-kB pathway proteins, and inhibit the expression of INF-β and NF-kB, suggesting that TRIM69 may participate in innate immune regulation. However, its function and mechanism in the innate immunity regulation of testicular antivirus is not clear. The purpose of this study is to clarify the function and mechanism of TRIM69 in the innate immune regulation of testicular antiviral, and to provide novel clues for the prevention and treatment of male infertility caused by virus infection.

病原体感染与炎症是导致男性不育的重要因素。睾丸是典型的免疫豁免器官，容易受到多种病原体的感染，为了有效抵御病原体感染，睾丸建立了局部天然免疫防御机制。因此，阐明睾丸天然免疫防御机制对于感染相关的不孕不育疾病的防治具有重要意义。TRIM家族蛋白广泛参与天然免疫应答与调控，TRIM69是TRIM家族的一个新成员，其在免疫调控方面的功能研究还属空白。前期研究发现TRIM69特异表达于睾丸，可抑制TLR信号通路基因表达，可与NF-kB通路蛋白相互作用，可抑制INF-β和NF-kB的表达，提示TRIM69可能参与天然免疫调控，但其参与睾丸抗病毒天然免疫调控的功能与机制尚未研究。本项目拟建立睾丸病毒感染小鼠模型和细胞模型，阐明TRIM69在睾丸抗病毒天然免疫调控中的功能，揭示TRIM69调控睾丸细胞抗病毒天然免疫调控分子机制，为睾丸病毒感染相关的男性不育的防治提供一定的理论依据。

免疫调节与微生物感染、肿瘤等疾病紧密相关。众多研究证明免疫微环境在肿瘤发生、发展中发挥重要作用。恶性肿瘤是世界范围内对人类生命健康福祉影响巨大的病理因素，在中国肺癌、肝癌、胃癌、胰腺癌、乳腺癌等恶性肿瘤的发病率不断升高，死亡率也居高不下，极大地威胁人民生命健康。总书记指出要将人民生命健康放在首要位置。此外，目前肝癌的治疗手段和药物还非常有限。因此，开展肝癌病理机制研究，以期开发有效的诊疗手段具有重要的现实意义。本研究通过生物信息学手段对肿瘤数据库获取的海量信息进行针对性分析，筛选到EEF1E1基因，其在肝癌中的表达、功能和机制还不清楚。我们通过一系列实验研究，发现其在肝癌组织中高表达，其表达与肝癌的临床病理特征显著相关，其表达与肝癌的肿瘤免疫微环境相关，其表达水平与肝癌病人的预后效果显著相关，其可能通过EEF1E1/ATM/p53信号调控肝癌的发生、发展，具有重要的临床和科学意义。