III型干扰素IFN-λ通过STAT1非依赖的JAK2-AKT通路参与炎症性肠病TJ屏障调控的作用机制研究

肠上皮紧密连接（TJ）破坏是肠黏膜屏障损伤的关键标志，在炎症性肠病（IBD）的发病机制中具有决定作用。探索TJ损伤修复机制、寻找促进TJ屏障修复的靶点对IBD的治疗有重要意义。我们前期研究发现：III型干扰素IFN-λ可能通过促进TJ屏障修复来抑制IBD肠道损伤，但具体机制不清。JAKs-STAT1活化是IFN-λ的经典信号通路，但我们发现阻断STAT1的活化不影响其对TJ屏障的作用。最近研究显示IFN-λ可抑制AKT的活化。而AKT活化可负调控TJ屏障。故我们推测：IBD条件下，IFN-λ可通过STAT1非依赖的JAK2-AKT信号通路上调TJ蛋白的表达，维护TJ屏障功能，进而抑制肠道损伤。本研究拟建立不同的肠炎模型以及细胞炎症模型，观察IFN-λ对TJ屏障的保护作用；应用基因敲减和信号通路抑制剂等手段，阐明IFN-λ调节TJ蛋白表达的分子机制，为IBD防治提供新的研究思路和治疗措施。

Intestinal epithelial tight junction (TJ) destruction is a key marker of intestinal epithelial barrier injury, and plays a decisive role in the pathogenesis of inflammatory bowel disease (IBD). It is of great significance to explore the molecular mechanism of TJ injury repair and to find targets that can promote TJ barrier repair in the treatment of IBD. Previous work have found that IFN-lambda can inhibit intestinal injury under IBD conditions, possibly by promoting the repair of TJ barrier, but the specific regulatory mechanism is still unclear. JAKs-STAT1 activation is the classical signal pathway of IFN-lambda, but we found that blocking STAT1 activation does not affect its effect on TJ barrier. Recent studies have shown that IFN-lambda can inhibit the activation of AKT. AKT activation negatively regulates TJ barrier. Based on previous work, we speculate that IFN-lambda can regulate TJ protein expression through STAT1 independent JAK2-AKT signaling pathway, maintain TJ barrier function and inhibit intestinal injury under IBD. In this study, different animal models of intestinal inflammation and in vitro cell models were established to observe the protective effect of IFN-lambda on intestinal TJ barrier. The specific signaling pathways of IFN-lambda regulating TJ protein expression were elucidated by RNA interference and signal pathway inhibitors, so as to provide new research ideas and therapeutic measures for the prevention and treatment of IBD.