白三烯B4第二受体（BLT2）在调控创伤性脑损伤后肠黏膜屏障损伤中的作用机制研究

创伤性脑损伤（TBI）所致的应激状态下，肠黏膜上皮细胞紧密连接蛋白（TJ）结构受损，发生肠黏膜屏障功能障碍，造成肠源性感染，引发多器官功能障碍，但具体发病机制仍未阐明。前期研究发现BLT2受体参与维持各类组织的上皮屏障功能，并在DSS肠炎小鼠模型中通过未知机制发挥肠黏膜屏障保护作用。前期研究证实小鼠TBI后肠组织BLT2和TJ蛋白表达均降低。我们推测TBI后BLT2表达下调导致细胞间TJ蛋白结构受损，不能有效维持肠黏膜屏障功能，导致毒素渗透和细菌移位，引发临床重症。本课题拟利用Caco-2细胞、转基因小鼠、和Cre-LoxP系统构建的肠上皮特异性BLT2基因敲除小鼠，从组织-细胞-分子多层面探索TBI对肠上皮BLT2表达水平的影响，阐明BLT2受体调控TBI后肠黏膜屏障损伤的分子机制，探索BLT2受体激动剂在肠黏膜屏障修复中的应用前景，为肠黏膜屏障功能障碍的治疗提供新的干预靶点。

Traumatic brain injury (TBI) induces stress state and leads to intestinal mucosal epithelial cell tight junction (TJ) protein structure damage, intestinal mucosal barrier dysfunction, and enterogenic infection. Eventually, multiple organ dysfunction syndrome occurs. However, the specific pathogenesis has not been elucidated. Previous studies have found that BLT2 was involved in the maintenance of epithelial barrier function in various tissues, and played protective effect on the intestinal mucosal barrier through unknown mechanisms in a DSS-induced colitis mouse model. Previous studies have confirmed that the expression of BLT2 and TJ protein in the intestinal tissue of mice after TBI was reduced. We then speculate that down-regulation of BLT2 expression following TBI results in impairment in TJ protein structure between cells. As the intestinal mucosal barrier function cannot be effectively maintained, toxin penetration and bacterial translocation occur, which resulting in clinical critical illness. This project intends to explore the effect of TBI on the expression level of BLT2 in intestinal epithelium and elucidate the molecular mechanisms of BLT2 involved in regulating intestinal mucosal barrier impairment after TBI from tissue-cell-molecular level by using Caco-2 cells, transgenic mice, and intestinal epithelial tissue-specific BLT2 knockout mice, which constructed by a Cre-LoxP system. Application prospect of the BLT2 agonist in the repair of damaged intestinal mucosal barrier will be investigated. It will provide a new intervention target for clinical treatment of intestinal mucosal barrier dysfunction.