KCNE5调控RIPK1介导的炎症激活与细胞坏死在儿童炎症性肠病中的作用机制研究

炎症性肠病（IBD）是一种慢性炎症性肠消化道疾病，暂无根治方法。预实验发现一名儿童IBD患者钾离子通道辅助亚基KCNE5发生缺失突变，但其它患者肠上皮KCNE5却明显升高，提示KCNE5对肠道稳态维持具有重要作用。进一步研究发现KCNE5表达受炎症因子（TNF-α）诱导，其上调促进上皮细胞RIPK1-NFκB通路激活，但敲减KCNE5则促进细胞坏死。文献报道UC病人肠上皮细胞钾离子外流增加；钾离子参与炎症应答与细胞死亡过程。据此假设：肠道损伤通过KCNE5-RIPK1-NF-κB介导炎症信号通路放大；而缺失KCNE5则促进RIPK3-MLKL介导的肠道上皮坏死。本项目拟结合临床标本及动物实验，阐述KCNE5调控肠道上皮稳态的细胞及分子机制,为IBD临床治疗提供新思路和新的潜在靶点。

Inflammatory bowel disease (IBD) is a chronic nonspecific intestinal inflammatory disease which cannot radical cure. Preliminary experiments identified a novel stop gain mutation of KCNE5, an potassium channel ancillary subunit, in a ulcerative colitis (UC) patient, while KCNE5 was highly expressed in the epithelium of other UC patients, suggested that KCNE5 plays important role in maintaining intestinal homeostasis. Further studies showed that TNFα induced the expression of KCNE5 and upregulated the phosphorylation of RIPK1-NFkB pathway. Knockdown of KCNE5 promotes cell necroptosis. It is reported that potassium outflow of intestinal epithelial cells in UC patients was increased; potassium participated in the process of inflammatory response and cell death. Based on this, we hypothesis that intestinal injury was amplified through KCNE5-RIPK1-NFκB-mediated inflammation signaling pathway; and the absence of KCNE5 promotes RIPK3-MLKL-mediated intestinal epithelial necrosis. This project intends to combine clinical specimens and animal experiments to illustrate the cellular and molecular mechanisms of KCNE5 regulating intestinal epithelial homeostasis, and to provide new ideas and new potential targets for the clinical treatment of IBD.