Th2介导的JAK-STAT信号通路活化在肠内营养保护肠道粘膜免疫屏障中的作用机制研究

项目名称： Th2介导的JAK-STAT信号通路活化在肠内营养保护肠道粘膜免疫屏障中的作用机制研究

项目编号： No.81470797

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王新颖

作者单位： 中国人民解放军东部战区总医院

项目金额： 75万元

中文摘要： 肠粘膜免疫损害及菌群改变引发的肠屏障功能障碍是创伤及外科大手术等重症病人发生感染甚至导致死亡的重要原因。早期肠内营养有助于上调肠粘膜免疫效应分子，降低感染的发生，但其中涉及的具体机制尚不清楚。前期研究表明缺乏肠内刺激时，Th2类细胞因子分泌减少，JAK-STAT通路活化受抑，导致肠粘膜免疫功能受损。因此我们提出假设：Th2类细胞因子介导的JAK-STAT信号通路活化在肠内营养保护肠屏障功能中发挥重要作用，且肠内营养存在剂量阈值启动肠粘膜免疫效应上调。项目采用小鼠肠外和肠内营养模型，通过基因敲除、JAK蛋白激动和抑制干预、免疫荧光、高通量测序鉴定肠道菌种和体外细菌培养等技术，探讨不同剂量的肠内营养刺激下Th2类细胞因子、JAK-STAT信号通路蛋白、肠粘膜免疫和肠屏障功能变化及其间相关性，明确肠内营养保护肠粘膜免疫的阈值剂量和分子机制，为肠内营养的临床应用和重症病人感染的防治提供理论依据。

中文关键词： 肠屏障；粘膜免疫；肠内营养；感染

英文摘要： Intestinal barrier dysfunction caused by the damaged intestinal mucosal immunity and the disruption of intestinal microflora balance is a main factor leading to infectious complication and even death of critically ill patients after trauma, infection and major surgery. Initial trophic enteral nutrition can maintain the intestinal mucosal immunity molecules and obviously decrease patients' infection morbidity, however, the exact mechanisms are still unclear. Previous evidence indicated that the decreased levels of Th2 cytokines due to the absence of enteral stimulation suppressed the activation of JAK-STAT pathway, and subsequently led to the dysfunction of intestinal mucosal immunity. We thus hypothesize that the activation of JAK-STAT pathway mediated by Th2 cytokines may play a crucial role in enteral nutrition protecting the intestinal mucosal barrier function and this process will be initiated when the dosage of enteral nutrition cross the threshold value. We investigate the changes and relationship among the levels of Th2 cytokines, the JAK-STAT pathway, intestinal mucosal immunity and intestinal barrier function in a mice model of parenteral and enteral nutrition, using gene knockout, intervention of JAK-1 agonist and inhibitor, immunological fluorescence, high-throughput sequencing and in vitro bacterial culture. We aim to explore the certain threshold dose of enteral nutrition upregulating the intestinal mucosal immunity and further discuss the underlying molecular mechanisms. Our results will provide rationale for the clinical enteral nutrition implementation and infection complication prevention in critical illness.

英文关键词： intestinal barrier;mucosal immunity;enteral nutrition;infection