蛋白激酶STK38L增强抗病毒天然免疫的机制及其在营养免疫调控中的作用

天然免疫在机体快速识别、清除病原、维持自身稳定过程中发挥重要作用，其中I型干扰素(IFN-I)通路介导的抗病毒天然免疫是机体对抗病毒感染的第一道防线。我们前期研究发现，蛋白激酶STK38L可显著增强病毒诱导的IFN-I表达，干扰STK38L可抑制IFN-I表达并促进病毒的增殖，然而STK38L作用的分子机制及其在动物体内的重要性尚不清楚。本课题拟通过多种分子生物学、免疫学实验技术研究STK38L增强IFN-I通路的分子机制，检测STK38L在小鼠IFN-I表达、病毒增殖、致病过程中的作用，分析其与临床病例病毒载量、症状的相关性，阐明其在抗病毒天然免疫中的重要作用。STK38L是Hippo-YAP通路的核心组分，而Hippo通路受细胞营养状态等因素调控，我们将进一步研究STK38L介导营养条件调控抗病毒天然免疫的作用。本项目将为开发新型抗病毒感染的药物和防治策略提供新思路。

The innate immune system is critical for the initial detection and elimination of invading pathogens. IFN-I (Type I Interferon)-mediated antiviral responses play crucial roles in resisting viral infection and maintaining body homeostasis. In our preliminary studies, STK38L (Serine/Threonine Kinase 38 Like) as an important protein kinase in the Hippo-YAP pathway, was initially identified to significantly potentiate IFN-I production in response to viral infection. Depletion of STK38L substantially reduced IFN-I levels thus allows an elevated viral proliferation. However, the in vivo significance of STK38L and its underlying working mechanism remains elusive. In this project, we will dedicated to investigate how STK38L mediates innate antiviral signaling by using gene knock-down and knock-in strategies, we aim to find the molecular targets of STK38L and elucidate their interplay, using comprehensively the molecular and immunological techniques. Moreover, we will also reveal the regulatory roles of STK38L in controlling IFN-I expression, viral proliferation and pathogenicity by studying STK38L knockout mice in vivo. The correlation between expression level of STK38L and the viral load and symptoms of clinical cases will also be evaluated. Diversified extracellular and intracellular signals, including nutritional status, orchestrate the Hippo-YAP pathway. STK38L has been identified as a core component of Hippo-YAP pathway. Thus, we will further clarify the role of STK38L in nutritional modulation of innate immune response. Upon successful conclusion of this work, we will clarify the new regulatory mechanisms of innate immunity, and provide new ideas for the prevention and treatment of viral infection.