新近研究显示，肠道黏液屏障阻止细菌接触肠道上皮细胞，因此在UC的发病中有重要作用，一旦细菌穿透肠道受损的黏液层内层，即可促发炎症反应。黏蛋白及肠道离子转运体DRA、NHE3是影响黏液层内层功能的重要因素，然而，何为其使动调控因素尚无定论。本小组前期研究显示，早期危险信号分子HMGB1蛋白可通过直接结合的方式抑制NHE3表达，或通过激活TLR4-MyD88途径抑制NHE3、MUC2表达功能。因此，本项目主要采用结肠活检组织离体培养+干预及荧光颗粒法、细菌探针法黏液层内层检测技术，在UC患者及对照肠道活检标本中研究HMGB1对肠道黏液层内层功能及肠道炎症的影响，并应用基因敲除小鼠研究HMGB1-TLR4-MyD88途径及其所调控的因素如NHE3对黏液层内层功能的影响，最后研究应用HMGB1-siRNA从源头阻断HMGB1对黏液屏障及肠道炎症的影响，以期为UC提供新的干预策略。

Recent studies have shown that UC is not triggered by the immune response against pathogens, but by the priming of the immune response to the normal intestinal flora. Intestinal mucus barrier is essential to prevent the interaction between bacteria and the intestinal epithelial cells, therefore has an important role in the pathogenesis of UC. Once the bacteria penetrate the inner mucus layer, intestinal inflammation is triggered. Mucins such as MUC2 and intestinal ion transporters such as DRA, NHE3 are important factors affecting inner mucus layer function. However, the initial regulatory factor for impaired inner mucus barrier is not yet understood. Our preliminary study shows that early stage danger signal HMGB1 protein can suppress NHE3 by direct combination of it, or inhibit NHE3 and MUC2 expression by activation of TLR4-MyD88 pathway. Therefore, this project aims at: firstly, to study the effects of HMGB1 on intestinal mucus barrier function and intestinal inflammation in UC patient as well as control colonic biopsies using in vitro tissue culture and inner mucus layer detection techniques. Secondly, to study the regulatory effect of HMGB1-TLR4-MyD88 pathway and NHE3 on the function of the inner mucus layer by application of knockout mice. Finally, to apply HMGB1-siRNA to block HMGB1 from the source to see the regulatory effect on mucus barrier and intestinal inflammation, so as to provide new therapeutic strategies for UC.