NDRG2调控肠道黏膜屏障在炎症性肠病发生发展过程中的功能和机制研究

Inflammatory bowel disease (IBD) is a set of recurrent episodes of chronic inflammatory intestinal diseases with unknown cause. Intestinal mucosal barrier is the important defense system against the environmental invasion of pathogenic microorganism. Mucosal barrier dysfunction predisposes to intestinal mucosa damage, increases intestinal permeability and immuno-dysregulation to induce IBD occurrence. However, it’s obscure about the regulation mechanism of intestinal mucosal barrier. Our group firstly reported and engaged in the study of new tumor-suppressor gene NDRG2 for a long time. For the first time we confirmed that NDRG2 was a novel biomarker for colorectal cancer prognosis. Recently, we established the intestinal epithelial cells specific ndrg2 knockout mice (Vil-Cre; ndrg2fl/fl) and found ndrg2 knockout prompted the adhesion connection defect of intestinal epithelial cells and mucosal barrier dysfunction, exacerbated the inflammatory bowel disease induced by DSS, strongly suggesting ndrg2 play an important protective role in the process of IBD development. This project plans to further use the ndrg2 knockout and knockin mouse, and establish both of DSS and TNBS induced IBD mouse model. We will elucidate how ndrg2 regulating the biological function, structure and molecular mechanism of intestinal mucosa barrier during IBD development. And also we will analyze the clinical significance of NDRG2 in IBD tissue samples. Our study will provide novel drug targets for the treatment of IBD.

炎症性肠病（IBD）是一组原因未明反复发作的慢性炎症性肠道疾病。肠黏膜屏障作为机体的重要防御体系，其功能障碍易诱发肠道通透性增加、免疫调节紊乱等病理反应，是IBD发生的重要诱因。但肠黏膜屏障的分子调控机制并不完全清楚，亟需深入研究。申请人课题组首次报道并长期从事新抑癌基因NDRG2功能研究，取得了一系列创新性发现。我们近期构建了肠上皮细胞特异性ndrg2 knockout小鼠，发现其肠上皮细胞间粘附连接结构受损和黏膜屏障功能障碍，并加剧DSS诱导的肠道炎症反应，强烈提示ndrg2在IBD发生发展过程中发挥重要的保护作用。本项目拟进一步利用ndrg2 knockout和knockin小鼠，分别建立DSS和TNBS诱导的小鼠肠道炎症模型，阐明ndrg2调控肠黏膜屏障的生物学功能，解析ndrg2的分子作用机制；并进一步利用IBD临床组织标本，揭示其临床意义，为IBD治疗提供新的药物作用靶点

炎症性肠病（IBD）是一组原因未明反复发作的慢性炎症性肠道疾病。肠黏膜屏障作为机体的重要防御体系，其功能障碍易诱发肠道通透性增加、免疫调节紊乱等病理反应，是IBD发生的重要诱因。但肠黏膜屏障的分子调控机制并不完全清楚。申请人课题组首次报道并长期从事新抑癌基因NDRG2功能研究，利用肠上皮细胞特异性ndrg2 knockout小鼠，发现其肠上皮细胞间粘附连接结构受损和黏膜屏障功能障碍，并加剧DSS诱导的肠道炎症反应，强烈提示ndrg2在IBD发生发展过程中发挥重要的保护作用。本项目在实施过程中，分别建立了DSS和TNBS诱导的小鼠肠道炎症模型，发现NDRG2在肠上皮的表达缺失，可以明显加剧肠道炎症反应，表现为肠道组织炎症加重、肠道长度缩短更显著、组织中炎症细胞浸润和炎症因子表达增加等。分析显示，NDRG2在肠上皮的表达缺失可以降低E-cadherin的表达，破坏细胞间粘附链接的结构完整性，最终导致肠道的通透性增加和炎症反应。进一步的分子机制研究显示，NDRG2可以通过增加E3泛素连接酶FBXO11与Snail的结合，促进Snail降解，进而增加E-Cadherin的含量。而NDRG2的缺失则会上调Snail的稳定性和蛋白含量，导致E-Cadherin的表达减少。我们利用AOM/DSS模型进一步建立了小鼠肠道炎癌转化模型，发现NDRG2的表达缺失可以促进肠道炎症肿瘤的转化进程。最后，我们利用临床IBD患者组织标本，发现NDRG2的表达水平与炎症水平和巨噬细胞的浸润呈负相关，进一步证实NDRG2在IBD发生过程中发挥保护效应。课题如期完成，在课题实施过程中共发表6篇SCI论文，申请获得国家发明专利1项，培养了3名博士生和2名硕士生。申请人获得中华医学会青年科技奖。