MiR-193a-3p调控结肠上皮PepT1表达在溃疡性结肠炎发病机制中的作用

There is strong evidence that the expression of PepT1, an epithelial di/tripeptide membrane transporter, is associated with the pathogenesis of ulcerative colitis (UC). However, this is little knowledge about their regulatory mechanisms. We have found that the expression of microRNA, miR-193a-3p, was reduced in colonic tissue in patients with active UC and the expression of of PepT1 was increased significantly at the same time. MiR-193a-3p regulates the expression of PepT1 through a post-transcriptional regulation. In the current proposal, we hypothesize that, in active UC, miR-193a-3p up-regulates the expression of target gene PepT1, induces intestinal immune responses and exacerbates inflammation. The aims of the study are to determine: 1) The relationship of the expression of miR-193a-3p and PepT1 in involved colonic tissue in UC patients and the activity of disease; 2) whether miR-193a-3p regulates PepT1 gene expression in intestinal epithelial cells; 3) whether over-expression of miR-193a-3p will lead to inhibition of the expression and function of PepT1; 4) whether over-expression of miR-193a-3p will improve inflammation and colitis in an animal model of UC. By studying the mechanism of microRNA regulating of target gene expression, we will gain knowledge of the pathogenesis of UC and find potential therapeutic targets

溃疡性结肠炎(UC) 发病与肠道寡肽转运体(PepT1)表达异常有关，但具体机制不明。我们首次发现UC患者肠道病变组织中miR-193a-3p表达水平较正常人明显降低，而PepT1蛋白表达显著升高，并预测和初步验证了PepT1是miR-193a-3p调控的靶基因；因此我们推测，在UC中miR-193a-3p通过对其靶基因PepT1的上调作为促发因素，诱导并加重肠道炎症及自身免疫反应。本研究将探讨组织miR-193a-3p和PepT1蛋白与疾病活动程度的关系，并进一步探讨miR-193a-3p表达对PepT1的靶向调控作用及这种靶向调控关系是否引起结肠上皮微环境的改变，激活免疫系统；是否可通过过表达miR-193a-3p来抑制PepT1的表达及功能，对肠道炎症实施干预逆转，从而起到治疗作用。本研究将有助于阐明miRNA调控相关靶基因在UC发病机制中的作用及潜在治疗靶点。

溃疡性结肠炎(UC) 的发病与肠道寡肽转运体(PepT1)表达异常有关，但其具体调控机制不明。我们发现UC患者肠道病变组织中miR-193a-3p的表达水平较正常人明显降低，并通过生物信息学计算预测并初步验证了PepT1是miR-193a-3p调控的靶基因；而PepT1可介导肠道中的炎症肽类物质进入肠道上皮细胞内，激活肠道免疫系统。本研究将探讨结肠上皮细胞中miR-193a-3p的表达对PepT1的靶向调控作用及这种靶向调控关系是否引起结肠上皮微环境的改变，激活免疫系统；是否可以通过过表达miR-193a-3p来抑制PepT1的表达及功能，对肠道炎症实施干预逆转，从而起到治疗作用。实验数据显示，miR-193A-3P参与了IBD的发病机制，至少在一定程度上通过靶向调控肠道内的PEPT1抑制细菌产物的吸收，从而达到减少通过NF-kB信号通路激活的宿主免疫反应；将miR-193a-3p转运至DSS诱导的肠炎小鼠肠道内可有效改善肠内炎症程度。综上所述，本研究为miR-193a-3p可成为IBD潜在治疗靶点提供了一定的理论基础。