CARD9 S12N变异在炎性肠病中的作用及机制研究

Multiple GWAS studies revealed a single nucleotide polymorphism (SNP) at rs4077515 in human genome, which results in a single amino acid substitution of CARD9, pSer12Asn, namely, CARD9 S12N, is associated with several inflammatory diseases, among which, inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC) are the most relevant. However, the function and mechanism of this mutation in IBD remain unclear. To unravel its function importance in IBD, we successfully generated CARD9 S12N knock in (KI) mice, and established two intestinal colitis models in these mice. We found in both models, CARD9 S12N contributed to susceptibility of colitis with increased inflammation in KI mice. Our previous study showed that CARD9 S12N is a gain-of-function mutation in Aspergillus fumigutas induced allergic bronchopulmonary aspergillosis (ABPA) development, by activating non-canonical NF-κB RelB pathway, turning alveolar macrophages into IL-5-producing cells and facilitates Th2-mediated pathologic responses. In this project, we will investigate the role of CARD9 S12N in regulating immune responses and in pathogenesis of IBD, among which, we will focus on the critical cells and effector molecules involved in this process and the molecular mechanism of CARD9 S12N in regulating immune response; in addition, we will investigate the function of CARD9 S12N in IBD by exploring pathogens-induced CARD9 degradation. The complement of this project will help us better understanding regulation of intestinal immune responses and the pathogenesis of IBD, providing a new therapeutic target and strategy for these kinds of diseases.

多项GWAS研究报道CARD9 S12N变异是炎性肠病(IBD)的易感因素，但其功能和作用机制不清。其在IBD中出现率高，且远高于在健康人群中的比例。为了研究其功能，我们构建了CARD9 S12N基因敲入小鼠，并发现在建立的两种肠炎模型中，该变异均使小鼠对肠炎易感，肠道炎症增强。我们前期研究发现其在烟曲霉菌诱导的过敏性支气管肺曲霉病发病过程中，可激活非经典NF-κB RelB信号通路，引起Th2免疫应答。本项目中，我们将研究CARD9 S12N变异对肠炎发病及肠道免疫应答的影响，重点关注CARD9 S12N参与肠炎发病中的关键免疫细胞类型、效应因子及其影响免疫应答的分子机制；我们还将从病原菌是否通过影响CARD9的稳定性和降解来逃避免疫清除，加速疾病的发生这个角度阐述其促进肠炎发病的机制。该项目的完成将有助于阐明肠道免疫应答调节及肠炎的发病机制，为IBD疾病诊治提供新的分子靶标和治疗策略。

多项GWAS研究报道CARD9 S12N变异是炎性肠病(IBD)等的易感因素，但其在疾病中的功能及作用机制并不清楚。通过本项目我们发现中国人中携带该突变的IBD人群占比非常高，远高于健康人群中的比例。为了研究CARD9 S12N在炎性肠病发病中的功能和作用机制，我们在国际上首先成功构建了CARD9 S12N KI小鼠，并在该小鼠中成功建立了肠炎模型。我们在两种模型中均发现该变异使小鼠对肠炎易感，肠道炎症增强。在一种肠炎小鼠模型中，我们发现CARD9促进肠炎发生的机制为1）抑制了巨噬细胞清除病原体的能力；2）通过影响固有免疫细胞继而影响了下游的适应性免疫应答反应。该项目的完成将有助于阐明肠道免疫应答调节及肠炎发病机制，为日益严峻的IBD疾病诊治提供新的分子靶标和治疗策略。