COUP-TFII靶向miR-34a/Snail环路调控Claudin-7表达在溃疡性结肠炎肠道上皮屏障功能中的作用研究

肠道上皮屏障功能异常是溃疡性结肠炎发病的重要始动因素。由Claudin家族构成的紧密连接是肠上皮屏障的主要成分，研究表明Claudin表达异常与溃疡性结肠炎密切相关。课题组前期发现COUP-TFII敲除小鼠肠道Claudin-7表达明显增高，较野生型小鼠不易诱导溃疡性结肠炎发生，并结合我们已经发表的研究进一步提示miR-34a/Snail负性调控环路可能是介导COUP-TFII作用的重要下游通路。本项目拟结合临床样本、COUP-TFII敲除小鼠，利用CRISPR/Cas9等技术，研究COUP-TFII在调控溃疡性结肠炎肠道上皮屏障功能异常中的作用，同时联合体外实验明确miR-34a/Snail与下游Claudin-7在这一过程的桥梁作用。该项目研究完成将阐明COUP-TFII调控溃疡性结肠炎发病中肠道上皮屏障功能异常的全新分子调控机制，从而可能为该疾病的治疗提供新的靶点。

The destruction of gut epithelial barrier function constitutes one major factor for pathogenesis of ulcerative colitis. The tight junction formed by claudin family members and other molecules is responsible for integrity of the barrier function. Studies have shown that aberrant expression of claudin is associated with ulcerative colitis. The preliminary results suggested that COUP-TFII genetic deficiency was associated with downregulated claudin-7 expression and attenuated inflammation. In addition, our previous studies revealed that miR-34a/Snail negative signaling loop was critical in mediating the downstream effect of COUP-TFII. This project aims to investigate the role of COUP-TFII in gut epithelial barrier function of ulcerative colitis by using clinical sample analysis, genetic engineering mouse model, and other techniques including CRISPR-Cas9. Furthermore, the mechanism for COUP-TFII function mediated by miR-34a/Snail and claudin-7 was determined through in vitro experiments. This work is helpful in delineating a novel molecular mechanism for regulation of intestinal barrier function in ulcerative colitis, and is expected to provide new target for development of therapeutic strategies.