HIF-2α通过NOTCH信号通路调控T细胞分化参与溃疡性结肠炎发展的机制研究

Ulcerative colitis (UC) is a non-specific inflammatory disease of intestinal tract. The pathogenesis of ulcerative colitis (UC) is unclear; th2 type inflammatory response is the main type of UC. It’s known that intestinal mucosal injury and repair process is accompanied by intestinal mucosal oxygen supply disorders. Hypoxia-inducible factor (HIFs) involved in the regulation of hypoxia adaptability is an important pathophysiological process during UC, the role of HIF-2α is controversial. Our pre-experimental study found that intestinal submucosal HIF-2α expression and mucosal injury were negatively correlated in UC patients. Furthermore, the expression of HIF-2α in T cells gained the highest stability under mild anoxic condition, and T-cell HIF-2α protected DSS-induced intestinal inflammation in animal models. After specific knockout of HIF-2α in T cells, the differentiation bias of intestinal submucosal T Cells towards Th2 secretion type was found. The aim of the present study is to investigate the mechanism of T-cell HIF-2α regulating Th2-secretory differentiation by Pull-Down, flow cytometry and animal modeling. The study is also aimed at demonstrating that T-cell HIF-2alpha can inhibit NOTCH signal and elucidating the protective mechanism of T cell HIF-2α on UC mucosal injury, and providing a basis for further understanding of the pathogenesis and remission mechanism of UC.

溃疡性结肠炎（UC）是表现为Th2型炎症反应的肠道非特异炎症性疾病，肠黏膜损伤及修复过程中伴随着氧供失调，缺氧诱导因子（HIFs）参与的缺氧适应性调节是其重要调控机制之一，其中HIF-2α的作用尚有争议。前期预实验发现UC患者肠黏膜下HIF-2α的表达和黏膜损伤呈负相关；T细胞内的HIF-2α在轻度缺氧条件下表达最高；T细胞内的HIF-2α对DSS诱导的小鼠肠道炎症具有保护作用；特异性敲除T细胞内HIF-2α后小鼠肠黏膜下Th0细胞向Th2细胞分化偏移，使Th2型炎症反应加重。我们设想：HIF-2α的作用存在细胞差异，T细胞内的HIF-2α能够通过抑制NOTCH信号通路减少Th0向Th2细胞的分化偏移，从而减轻肠道炎症。本项目拟借助Pull-Down、流式细胞术、动物造模等实验深入研究T细胞内HIF-2α调控Th2细胞分化的分子机制，为进一步阐明缺氧参与UC发病、缓解的机制提供理论基础。