低氧微环境下成纤维样滑膜细胞（FLS）迁移侵袭是类风湿关节炎（RA）滑膜病变进展的关键环节。我们报道蛋白质二硫键异构酶TXNDC5在RA滑膜组织高表达，促进RA-FLS迁移，但机制未明。预实验发现低氧状态下TXNDC5表达上调并调控泛素连接酶SIAH2；且低氧和TXNDC5 PDI酶活性在TXNDC5与SIAH2结合中起重要作用。由此推测低氧微环境下TXNDC5发挥PDI酶活性调控SIAH2促进RA-FLS迁移侵袭参与RA进展。本课题拟从分子、细胞、动物、组织多层次：揭示低氧微环境下TXNDC5对RA进展的作用及信号通路；明确TXNDC5与SIAH2的结合位点，分析TXNDC5对SIAH2二硫键形成和泛素化作用的影响；探讨TXNDC5在RA滑膜中的表达特点及与临床指标的关联。阐明TXNDC5作为关键枢纽蛋白连接低氧和泛素化作用参与RA进展的机制，为寻找RA治疗新靶点提供依据。

Fibroblast-like synoviocytes (FLS) in synovial intimal lining of the joint play a pivotal role in the pathogenesis of rheumatoid arthritis (RA) through migration and invasion under hypoxia. TXNDC5 (thioredoxin domain-containing protein 5) encodes a member of protein disulfide isomerase (PDI) family that catalyze disulfide bond formation, isomerization and reduction. We reported that TXNDC5 is highly expressed in synovial membranes of RA, and promotes migration of RA-FLS. However, the pathological mechanism of TXNDC5 has not been well characterized.. Our preliminary data showed that: (1) Isobaric tags for relative and absolute quantification (iTRAQ) analysis reveals that TXNDC5 regulates E3 ubiquitin ligase SIAH2 in response to hypoxia; (2) The interaction between TXNDC5 and SIAH2 is responsive to hypoxia and TXNDC5 PDI activity. Based on the above data, we hypothesize that TXNDC5 contributes to migration and invasion of RA-FLS by regulating E3 ubiquitin ligase SIAH2 under hypoxia in rheumatoid arthritis.. The research will be carried out from smallest to largest including different levels, such as molecule, cell, animal, tissue, etc. We intend to: (1) reveal the contribution and pathway of TXNDC5 in promoting RA progression under hypoxia; (2) determine the binding site between TXNDC5 and SIAH2; meanwhile, analyze the regulatory effect of TXNDC5 to SIAH2 in disulfide bond formation and ubiquitination; (3) illuminate the expression pattern of TXNDC5 and SIAH2, evaluate the correlation between TXNDC5 expression and clinical index. Base on the above research, we explore the mechanism of TXNDC5, as a key pivotal protein between hypoxia response and ubiquitination, promotes progression of RA. This proposed research will determine the feasibility of TXNDC5 as a therapeutic target against RA.