线粒体抗病毒信号蛋白MAVS在急性肺损伤中的作用和机制研究

急性肺损伤是高发病率和高致死率的呼吸系统疾病，其发病机制尚未完全明确，且缺乏有效的临床治疗策略。MAPK信号通路调控急性肺损伤过程细胞活化和炎症反应，研究其详细调控机制对该疾病的防治意义重大。我们的前期研究提示MAPK核心激酶ASK1可被线粒体抗病毒信号蛋白MAVS结合调控，MAVS在急性肺损伤进程中显著下调，但MAVS对急性肺损伤的作用和机制目前尚不清楚。本项目前期研究发现，MAVS敲除小鼠促进脂多糖诱导的肺脏ASK1和下游MAPK激活，加重肺水肿和炎症反应。本项目假设MAVS可通过抑制MAPK信号通路激活保护急性肺损伤。本研究拟通过单细胞RNA测序明确MAVS发挥功能的细胞群；通过基因工程小鼠的疾病模型，结合多组学分析和分子生物学实验，阐明MAVS调控急性肺损伤的功能和机制。本项目将揭示MAVS调控急性肺损伤的作用和机制，扩展MAVS的生物学功能，为该疾病药物开发提供新靶点和新策略。

Acute lung injury (ALI) is a prevalent respiratory disease with high risk of mortality. However, its underlying mechanism still poorly understood and therapeutic approach is limited. MAPK signaling pathway is critical in regulating cell activation and inflammatory response during ALI. Exploring detailed mechanism of MAPK signaling in the pathophysiology of ALI is utmost important for seeking therapeutic target this devastating disease. Our previous study found that ASK1, a apical MAPK kinase, can be recognized and regulated by mitochondrial antiviral signaling protein MAVS. MAVS is significant suppressed in ALI and its role in ALI is unknown. MAVS deletion further potentiated lipopolysaccharide induced pulmonary edema, inflammatory response and MAPK signaling activation in mice models. Thus, we hypothesis that MAVS suppresses MAPK signaling pathway and play a protective role in ALI. In this project, we aimed to identify the cell types directly regulated by MAVS by single cell RNA sequencing, and clarify the function and mechanism of MAVS in regulating ALI using the genetically engineered mouse disease model, combined with multiomics analysis and molecular biology experiments. The achievements of this project will reveal the function of MAVS in ALI, expand the biological function of MAVS, and pave the way for developing therapeutic strategies to treat ALI.