运动应激下PHD2/HIF-1信号途径在肠上皮细胞调控天然免疫防御中的机制研究

肠上皮细胞具有包括识别病原相关分子模式和释放抗菌肽进行免疫防御等重要的天然免疫调节功能。研究发现，中小强度运动促进肠道的免疫监视，大强度运动增加肠道通透性引发炎症反应。运动中血液重分配，消化道血液灌流量减少，组织间含氧量下降。低氧诱导因子-1(HIF-1)在肠黏膜屏障损伤修复及免疫调节中起重要作用。辅氨酰羟化酶PHD2通过介导泛素化控调的HIF-1降解。因此，我们推测运动应激通过PHD2/HIF-1信号途径影响肠上皮细胞天然免疫防御功能。本项目拟使用C57BL/6小鼠、肠上皮细胞特异性敲除PHD2和HIF-1α的基因敲除小鼠，探索运动应激对肠上皮细胞调控天然免疫防御的影响；通过肠干细胞3D培养技术，构建小肠类器官(organoid)，探索PHD2/HIF-1信号途径参与肠上皮细胞天然免疫调节的机制。本项目为深入了解运动调控肠粘膜免疫稳态提供实验依据，并为功能性胃肠病的运动干预提供新思路。

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-1 (HIF-1) plays an important role in the regulation of intestinal barrier function during exercise. To test this hypothesis, 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. 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.