ANP抑制“相变”触发cGAS-STING通路调控IBD肠道黏膜免疫激活

IBD发病关键是肠道菌群引起过度免疫应答，但具体机制不明。cGAS-STING是新的固有免疫信号通路，通过识别细胞质内dsDNA发挥免疫防御；一种新的无膜细胞器——“相变”参与了dsDNA与cGAS结合及活化，“相变”的发现是细胞物理化学领域的一个里程碑。基于前期研究我们推测，细菌dsDNA可能通过与肠道固有免疫细胞内cGAS形成相变，触发STING介导的肠粘膜免疫激活。调控相变可能从源头抑制过度的免疫应答。ANP是新的激素类细胞因子，可调控dsDNA 与cGAS相变形成的关键底物，我们发现ANP负调控IBD炎症，由此推测，ANP通过调节相变抑制肠道细菌激活cGAS-STING通路，下调IBD肠道炎症。本课题采用荧光漂白、活细胞成像延时摄影等手段，从分子、细胞和整体水平阐明细菌dsDNA通过相变激活肠道粘膜免疫具体过程及ANP对该过程的调控，探索新的治疗策略。

The key to the pathogenesis of IBD is that the gut microbiota induces excessive immune response . However, the specific mechanism underlying the microbiota induced excessive immune response remains unknown. cGAS-STING is a new innate immune signaling pathway that exerts immune defense by recognizing dsDNA in the cytoplasm; A new type of membraneless organelle——phase transition is involved in binding of dsDNA and cGAS and then activation.The discovery of phase transition is a milestone in the field of Cellular Physical Chemistry. Based on previous studies, we speculated that bacterial dsDNA may trigger STING meidiated intestinal mucosal immune activation by forming phase transition with cGAS in the intestinal innate immune cells. Regulating phase transition may inhibit excessive immune responses from the beginning. ANP，which is a new hormone cytokines, is essential for regulating the formation of dsDNA and cGAS phase transition. We found that ANP is involved in the activation of IBD inflammation. Therefore, we supposed that ANP inhibits bacterial triggering cGAS-STING pathway through negative regulation of phase transition and then down-regulates IBD intestinal inflammation. In this project, we take fluorescence recovery after photobleaching (FRAP),live cell imaging Time-Lapse photography and other means to clarify the specific process of bacterial DNA activating intestinal mucosal immune by phase transition from the molecular, cellular and in vivo levels, and the regulation of ANP on this process, so as to explore new therapeutic strategies for IBD.