OGT调控STAT1糖基化修饰及IFN介导的抗病毒功能的机制研究

IFN是先天免疫以及机体抵抗病毒感染第一道防线中最重要的细胞因子。目前，IFN依然是临床治疗多种病毒感染疾病的常规疗法。近年来，随着人们物质生活的极大丰富，糖尿病患病率急剧增加，糖尿病患者中IFN抗病毒治疗效果不佳。重要的是，在糖尿病人和动物模型中糖基化水平明显增高；然而，糖基化修饰与IFN介导的抗病毒功能的研究尚未有报道。本项目在前期的研究中发现糖基转移酶OGT能够与STAT1结合，显著抑制IFN信号通路，降低IFN介导的抗病毒效率。在此基础上，本项目拟深入探讨糖基转移酶OGT对STAT1的糖基化修饰；进一步，明确糖基化修饰对IFN信号通路和抗病毒功能的影响；最终通过敲基因小鼠研究糖基化修饰对体内抗病毒反应的影响。本项目通过探索糖基化修饰调控IFN抗病毒信号的新机制，旨在为临床抗病毒治疗提供潜在的分子靶标。

IFN is the most important cytokine in innate immunity and the first line of defense against viral infection. At present, IFN is still a routine therapy for the treatment of a variety of viral infections in clinical. In recent years, as people's material life is greatly enriched, the prevalence of diabetes has increased sharply, and IFN antiviral therapy is not effective in diabetics. Importantly, the O-GlcNAcylation levels are significantly increased in diabetics and animal models; however, it has not been reported about the relevance between O-GlcNAcylation modification and IFN-mediated antiviral function. Our preliminary datas showed that the glycosyltransferase OGT interacted with STAT1 and significantly inhibited IFN signaling pathway, which reduced IFN-based antiviral therapy efficacy. Based on a series of our preliminary datas, we plan to explore STAT1 O-GlcNAcylation modification by OGT. Further, we will study the mechanisms by which OGT regulates IFN signaling pathway and IFN-mediated antiviral function. Finally, we intend to clarify the influence of antiviral function by O-GlcNAcylation modification through knockout mice. This project focuses on studying the new mechanisms by which protein O-GlcNAcylation modification regulates IFN antiviral signaling and function, and aims to provide potential therapeutic targets for antiviral therapy.