类风湿关节炎RA是一种临床最常见的疑难顽症，其发病机制仍不十分清楚。滑膜成纤维细胞RASF、Th17细胞、toll样受体及其介导的炎症反应在RA发病中发挥重要作用。研究表明，RA患者关节腔及滑膜组织长期处于缺氧状态。本课题组前期研究证实，缺氧可以协同TLR3通路活化RASF分泌更多炎性因子，并可以促进RA患者PBMC中IL-17的表达，抑制Foxp3的表达。在此基础上，本项目拟利用RASF及RA T细胞作为模型，率先系统性探讨缺氧及缺氧诱导因子HIF-1α介导的促炎反应的作用，重点探讨其对RASF中TLR通路介导的炎症反应的协同作用；对RA患者Th17细胞的诱导分化作用；以及对RASF-T细胞相互作用的放大效应，揭示其在RA发病中意义，并进一步首次探寻以HIF-1α为靶标的RA治疗新策略的可行性。这一研究将在分子水平对RA发病机制的认识产生重要影响，并为RA治疗寻找新的免疫靶标。

Rheumatoid arthritis (RA) is one of the most difficult diseases in the clinic. Nevertheless, its pathogenesis still remains unclear. Rheumatoid arthritis synovial fibroblasts (RASF), Th17 cells, as well as toll-like receptors play important roles in the pathogenesis of RA. It is proved that the joint cavity and synovial tissues of RA patients are contantly under hypoxic conditions. Our previous studies have shown that hypoxia could synergize with TLR3 agonist polyIC to stimulate RASF to secrete more proinflammatory cytokines. More importantly, we found that hypoxia could promote IL-17 expression while compromise Foxp3 expression in PBMC of RA patients. Therefore, in this study, using RASF as well as RA patient T cells as models, we will systemically explore the role of hypoxia- and hypoxia-inducible factor-1α-induced inflammation in the pathogenesis of RA. We will focus on the synergistic effects of hypoxia on TLR signalling-induced inflammatory responses in RASF, the induction effects of hypoxia and HIF-1α on Th17 cell differentiation in RA patients, and the amplification effects of HIF-1α on RASF-T cell interaction. Furthermore, we will test the feasibility of targeting HIF-1α for RA therapy. This study will not only improve our understanding about the pathogenesis of RA on the molecular level, but also will provide new target for RA therapy.