近年来，我国及全世界炎症性肠病（IBD）的发病率逐年上升，而肠道微生态中的共生真菌维持肠道稳态发挥重要作用。天然免疫细胞中接头蛋白CARD9是C型凝集素受体介导抗真菌免疫的关键蛋白；近期多项GWAS研究提示CARD9蛋白S12N先天性变异与IBD发生显著相关，但缺乏直接证据。申请人前期成功构建CARD9 S12N突变的KI小鼠，并证明CARD9的S12N变异导致变态反应性肺曲霉菌病的发生（Nat Immunol 2018），还发现CARD9 S12N KI小鼠易感DSS诱导的结肠炎；以及该变异抑制了真菌表面α-甘露糖刺激DC中IL-10产生。本项目拟深入研究CARD9 S12N变异抑制DC中IL-10产生促进机体易感IBD的分子机制，阐明肠道共生真菌在IBD发生中的作用，并明确抗真菌免疫关键蛋白CARD9变异在IBD发生中的作用及机制，为IBD的临床诊断和精准治疗提供新的靶点和治疗策略。

The prevalence and incidence of inflammatory bowel disease (IBD) has gradually increased over the past decades in China and worldwide. Of note, intestinal symbiotic fungus performed pivotal roles in maintaining intestinal homeostasis. CARD9, mainly expressed in innate immune cells, is a central adaptor protein downstream of C-type lectins (CLRs) signaling for anti-fungal infections. Genome-wide association study (GWAS) analysis have suggested that inherited CARD9 S12N mutation is highly associated with development of IBD, but how and why CARD9 S12N mutation predisposes host susceptible to IBD is rarely reported. In previous work, we have generated CARD9 S12N knock-in (CARD9S12N KI) mice and demonstrated that CARD9S12N facilitated pathogenesis of allergic bronchopulmonary aspergillosi (Nat Immunol 2018). Moreover, we found CARD9S12N KI mice were susceptible to DSS-induce colitis, and that CARD9S12N downregulate IL-10 production in dendritic cells (DC) response to α-mannan stimulation. In this project, we aim to uncover the molecular mechanism of CARD9 S12N mutation negatively regulate IL-10 production in DC to predispose host susceptible to IBD; and then reveal the crucial role of intestinal symbiotic fungus in development of IBD; and finally definitude the role of CARD9 S12N mutation in development of IBD, which will provide new target and therapeutic implications for clinical diagnosis and precision therapy of IBD.