运动中HIF-1α对肠黏膜屏障的调控机制研究

项目名称： 运动中HIF-1α对肠黏膜屏障的调控机制研究

项目编号： No.31471135

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生理学与整合生物学

项目作者： 陈佩杰

作者单位： 上海体育学院

项目金额： 86万元

中文摘要： 肠黏膜屏障是机体抵御肠腔内病原微生物入侵的第一道防线。运动中血液重分配，内脏血液灌流量减少，使肠道区域一定程度缺氧。低氧诱导因子-1α（HIF-1α）在肠黏膜屏障损伤修复及免疫调节中起重要作用。研究表明，大强度运动损伤肠黏膜屏障，中小强度运动在一些疾病模型中保护肠黏膜屏障。因此，我们推测HIF-1α在运动中参与调控肠黏膜屏障。本课题拟通过生物发光活体成像技术在体观察运动中HIF-1α表达情况，运用Cre-LoxP系统构建肠上皮组织特异性HIF-1α与PHD2基因敲除小鼠，从器官-组织-细胞-分子多层面研究HIF-1α在不同强度运动中对肠黏膜屏障的调控机制。通过动物和人体实验，探索在大强度运动前通过调节HIF-1α含量而缓解肠黏膜屏障损伤的应用价值。本课题从肠黏膜屏障角度揭示中小强度运动对机体的保护作用，为深入了解大强度运动导致肠黏膜屏障损伤提供实验依据，并为肠黏膜屏障损伤的防治提供新思路。

中文关键词： 运动；HIF-1α；肠黏膜屏障；条件性基因敲除；低氧

英文摘要： Intestinal epithelial cells are positioned between an anaerobic lumen and a highly metabolic lamina propria, affected by reduced blood flow and tissue hypoxia. Intensified and prolonged exercise impairs the intestinal barrier, while mild to moderate exercise attenuates the intestinal barrier dysfunction in chronic stress mouse models. Exercise induces gastric ischemia, leading to intestinal tissue hypoxia. Therefore, we hypothesize hypoxia-inducible factor-1α (HIF-1α) plays an important role in the regulation of intestinal barrier function during exercise. To test this hypothesis, the noninvasive in vivo bioluminescence imaging is used to examine the HIF-1α expression in ROSA26 ODD-Luc/+ mice during different volumes of exercise. In order to investigate the function of HIF-1α in intestinal barrier during exercise with different intensity, conditional and intestinal epithelial cell-specific knock-out mice for HIF-1α and prolyl hydroxylase (PHD) 2 will been developed using the Cre-LoxP recombination system. The application value of PHD inhibition and hypoxic exposure on inflammation responses and intestinal barrier permeability will also be studied in mouse and human exhaustive exercise models. For the first time, this study explores the mechanisms of HIF-1α regulating the intestinal barrier function in response to exercise, providing experimental evidences for further study of intestinal barrier function during exercise.

英文关键词： exercise;HIF-1α;intestinal barrier;conditional gene target;hypoxia