溃疡性结肠炎(UC)中TNF-α可影响紧密连接蛋白表达破坏肠上皮屏障功能，但机制尚不清楚。本研究小组前期研究发现在TNF+/Δare转基因小鼠模型中TNF-α过表达可导致紧密连接蛋白表达异常、肠上皮通透性增加；而DRA过表达可影响紧密连接蛋白表达，部分恢复TNF-α引起的肠上皮屏障功能降低；进一步研究发现ATX-LPA轴在DSS诱导性小鼠结肠炎中对DRA的表达和上皮屏障重建有重要作用。结合前期研究和预实验结果，我们提出在UC中TNF-α经ATX-LPA轴调控DRA导致肠黏膜上皮屏障功能改变。本研究拟从临床和动物实验证实TNF-α、ATX和LPA调控DRA及紧密连接蛋白的表达，通过激活/阻断NF-κB途径和启动子激活在细胞水平进一步探讨TNF-α在ATX-LPA调控DRA过程中的信号通路和分子机制，阐明TNF-α-ATX-LPA-DRA在UC肠上皮屏障中的作用及意义，以期寻找潜在的干预靶点。

TNF-α could destroy intestinal epithelial barrier by affecting the expression of tight junction (TJ) proteins in ulcerative colitis (UC), but the detailed pathogenesis could not be clarified yet. Our previous study found that overexpression TNF-α in TNF+/Δare transgenic mice could affect TJ proteins expression leading to increased intestinal epithelial permeability, whereas Slc26a3 (DRA) overexpression could affect TJ proteins expression and restore the TNF-α-induced decrease of epithelial barrier, which means TNF-α induced TJ disruption is in part through its effect on the expression of DRA. Further studies showed that ATX-LPA axis has a central role in the expression of DRA in DSS-induced colitis mice and the process of intestinal epithelial barrier reconstruction. Based on the present theories and our experiments, we pose a hypothesis that TNF-α regulates DRA via ATX-LPA axis therefore leading to intestinal epithelial barrier function change. Thus, we intend to demonstrate the role of TNF-α、ATX and LPA in intestinal epithelial barrier, and the mechanisms of TNF-α-ATX-LPA regulates the expression of DRA and TJ proteins in clinical and animal colitis model. Furthermore, the possible signal pathway and molecular mechanism in the process of TNF-α regulating DRA via ATX-LPA axis will be investigated through activating or blocking NF-κB pathway and the promoter activation analysis in cellular level. In this way, we want to illustrate the role and mechanisms of TNF-α-ATX-LPA-DRA involved in intestinal epithelial barrier in ulcerative colitis, to explore the potential intervention targets of UC.