VDR-PPARγ自噬通路在三氧化二砷治疗类风湿关节炎中的作用

Rheumatoid arthritis is one of the most prevalent autoimmune diseases ultimately causing disability. The definite pathogenesis of RA is still unknown and there is a lack of effective and specific therapies without severe side effects. So it is imperative to find new drugs to treat RA. We first found the effect of arsenic trioxide (ATO) in treating RA and confirmed that it could promote synovial cell apoptosis as well as inhibit angiogenesis, but its mechanism remains to be further clarified. Pre-experiments showed that ATO could promote the expression of VDR and PPARγ mRNA in RA FLS. Therefore, we speculate that ATO show its protective effect through triggering the VDR-PPARγ autophagy pathway. To prove the hypothesis, we will conduct experiments in vivo and in vitro to detect the influence of ATO on VDR-PPARγ pathway and downstream genes; we will also conduct further observation of its combined effect with the agonist of VDR, 1, 25-dihydroxy vitamin D (VD). Our research will clarify the mechanism of ATO in RA treatment from a new angle, and lay a foundation for attenuated treatment and the combination therapy with VD.

类风湿关节炎（RA）是常见的自身免疫病，致残率高，但其确切机制不详，尚缺少有效、特异且副作用小的治疗手段，因此寻找新的治疗RA的药物也成为当务之急。我们在筛选治疗药物的过程中首先发现，三氧化二砷（ATO）对RA有治疗作用，并可促进滑膜细胞凋亡、抑制血管生成，但其治疗机制还有待进一步明确。预实验初步表明，ATO可使RA FLS中自噬相关基因VDR及PPARγ表达增加，故我们推测，ATO可通过VDR-PPARγ通路激活自噬，从而对RA起到治疗作用。为证明该假设，我们将分别从细胞及动物水平，检测ATO对VDR-PPARγ通路及下游自噬基因表达的影响，并在此基础上进一步观察ATO与该通路激动剂1,25-二羟维生素D (VD)联合作用的效果。本课题将从全新视角进一步阐明ATO治疗RA的机制，并为其与VD的联合应用及减毒治疗提供理论依据。

类风湿关节炎 (Rheumatoid arthritis, RA) 是一种以侵蚀性关节炎为主要表现的慢性、进行性、对称性自身免疫性疾病，目前临床上缺少有效疗法。我们研究发现三氧化二砷（ATO）对于RA的治疗具有一定的效果，其具体作用途径可以从多个方面进行解释。在RA患者及动物模型中，自噬流受损，体内外实验表明，ATO可激活滑膜细胞中维生素D受体 (VDR) -过氧化物酶体增殖物激活受体γ (PPARγ)自噬功能模块，PPARγ能够进一步影响下游PI3K/AKT/mTOR自噬信号通路，恢复受损自噬流，显著抑制炎性因子及分解代谢因子分泌，而ATO与维生素D具有联合作用也可为ATO的减毒治疗提供理论基础。此外，CD４＋T细胞的细胞亚群在RA疾病过程中发生变化，Treg/Th17细胞的失衡被认为是RA发生发展的重要因素，我们研究发现ATO通过靶向STAT3抑制Th17细胞分化而同时促进Treg细胞的产生，从而改善RA。我们从自噬、免疫等角度分别阐述ATO对RA疾病进程的影响，将为RA的后续治疗提供一定的理论基础。