C型凝集素受体相关的NF-κB信号通路在肠炎及肠癌发病过程中的分子机制研究

Colorectal cancer is a common gastrointestinal malignant tumors threatening human health. Patients with inflammatory bowel disease (IBD)- either Crohn’s disease (CD) or ulcerative colitis (UC) are at increased risk for developing cancers of the gastrointestinal tract, particularly colorectal cancer (CRC). Interactions between the commensal microbiota and the gut immune system are critical for establishing colonic epithelial homeostasis. Although the vast majority of studies on commensal microbiota have focused on gut bacteria, recent studies have begun to note the importance of commensal fungi in gut. A rich fungal community that interacts with the immune system was proved in mammalian gut. However, how commensal fungi interacts with immune system and whether this interaction affects colonic epithelial homeostasis remains unknown. Emerging evidence indicates that several mammalian C-type lectin receptors (CLRs) function as pattern recognition receptors (PRRs) for sensing fungal infections, and trigger multiple signaling cascades leading to expression of various pro-inflammatory cytokines and anti-microbial proteins..In our recent studies, we have found that Dectin-2 and Dectin-3, two CLRs, form a heterodimeric complex and function as a PRR for sensing fungal infection. Interestingly, in our preliminary studies, we found that Dectin-3 and CARD9 KO mice were more susceptible to DSS-induced colitis than wild type mice. C. tropicalis, which is an opportunistic fungal pathogen, was significantly increased in the colonic epithelial. Based on our preliminary studies, we propose to characterize the molecular mechanism by which Dectin-3 and CARD9 deficiency leads to altered immunity to commensal fungi in the gut; to determine how interactions between commensal fungi and Dectin-3 influence colitis; and to determine how Dectin-3/CARD9 signaling mediates colonic epithelial homeostasis. These lines of investigation will reveal molecular mechanism by which host innate immune system affect colonic epithelial homeostasis in response to commensal fungal dysbiosis, which will provide the molecular basis of potential therapeutic targets for designing adjuvant and vaccine against microbial dysbiosis in gut.

结肠癌是严重威胁人类健康的一类常见胃肠道恶性肿瘤。炎性肠病患者结肠癌发病率显著增高。研究发现，肠道系统中除细菌外存在很多真菌，但对于其如何与肠道免疫系统相互作用影响肠道系统动态平衡最终导致肠癌发生的机制尚不清楚。C型凝集素受体激活的NF-κB信号通路对真菌引起的免疫反应至关重要。.我们前期研究发现C型凝集素受体Dectin-3 或NF-κB激活的关键分子CARD9敲除的小鼠对DSS诱导的肠炎更易感， C. tropicalis是肠道系统中的主要真菌群。本项目从C型凝集素受体相关的NF-κB信号通路入手，探讨肠道系统中真菌激活的免疫信号通路，特别是CARD9依赖的NF-κB通路在DSS诱导的肠炎模型及DSS/AOM诱导的肠癌小鼠模型中影响肠道免疫系统并导致疾病的分子机制。这些问题的解决，有助于阐明肠道真菌与免疫系统相互作用影响肠病发生的分子机制，为日益严重的肠癌提供新的分子靶标和治疗策略。

结肠癌是严重威胁人类健康的一类常见胃肠道恶性肿瘤。炎性肠病患者结肠癌发病率显著增高。研究发现，肠道系统中除细菌外存在很多真菌，但对于其如何与肠道免疫系统相互作用影响肠道系统动态平衡最终导致肠癌发生的机制尚不清楚。C型凝集素受体激活的NF-κB信号通路对真菌引起的免疫反应至关重要。.本项目从C型凝集素受体相关的NF-κB信号通路入手，探讨肠道系统中真菌激活的免疫信号通路，特别是CARD9依赖的NF-κB通路在肠炎和肠癌小鼠模型中影响肠道免疫系统并导致疾病的分子机制。我们阐述了C型凝集素受体Dectin-3和下游信号通路重要蛋白CARD9及其突变体CARD9-S12N介导的真菌免疫在肠道稳态维持中的重要作用，发现了肠道共生真菌在炎症性肠病发病中的新型机制，对于临床肠道疾病的诊治具有重要意义；此外，还鉴定了Cbl-b和JNK两个抗真菌免疫负调控因子。这些问题的解决，有助于阐明肠道真菌与免疫系统相互作用影响肠病发生的分子机制，为日益严重的肠癌提供新的分子靶标和治疗策略。