miR-155上调自噬对重症急性胰腺炎小鼠肠黏膜屏障保护作用的实验研究

胰腺继发感染是重症急性胰腺炎（SAP）最严重的并发症,肠道是引发胰腺继发感染的主要来源。本课题组前期研究表明,体内炎症因子失控性释放是SAP肠粘膜屏障损伤的主要原因，最新研究发现自噬能抑制炎性体及其关键效应蛋白caspase-1的活化，减少IL-1β等炎症因子的释放，而自噬受TAB2的负性调控，miR-155能靶向沉默TAB2蛋白的表达。我们推测通过在肠上皮细胞内过表达miR-155来上调自噬，有可能成为抑制炎症介质释放的新途径。我们的前期工作已证实LPS刺激肺泡巨噬细胞后miR-155表达上调、细胞自噬增加。本项目拟体外转染miR-155入肠上皮细胞，分析它对TAB2/自噬/炎性体和炎症介质的影响，并将in vivo-jetPEI介导的miR-155静脉注入SAP小鼠模型中，探讨对SAP小鼠肠粘膜屏障损伤保护作用及其机制，为临床上基因干预SAP肠粘膜屏障损伤的可行性提供依据。

Secondary bacterial infection was the most serious complication of severe acute pancreatitis. The intestine was the the main source of the bacterial infection.Our preliminary studies shows that the uncontrolled release of inflammatory factors was the main reason of intestinal mucosa barrier damage.New research finds that inflammatory and caspase-1 activation are inhibited by autophagy, leading to decrease IL-1β release. Moreover, autophagy is negatively regulated by TAB2; up-regulation of miR-155 can down-regulate TAB2 expression. we have strong evidence that activation of macrophages by LPS induced miR-155 overexpression and enhanced autophagy. Based on these findings, we hypothesize that overexpression of miR-155 in the epithelial cells of intestinal mucosa might provide new strategy to block release of inflammatory mediators during severe acute pancreatitis. In this project, we will explore whether upregulation of miR-155 in epithelial cells of intestinal mucosa by transfection effects TAB2 expression, autophagy, caspase-1 and inflammatory mediators in vitro. Furthermore, we will take advantage of mouse severe acute pancreatitis model to examine whether miR-155 intravenous injection by in vivo-jetPEI protect intestinal mucosa barrier against injury, to investigate potential mechanisms. The success of such strategy will provide a novelty approach to treat intestinal mucosa barrier damage induced by severe acute pancreatitis.