1-磷酸鞘氨醇在类风湿关节炎滑膜血管新生中的作用及机制研究

Rheumatoid arthritis (RA) is an autoimmune disease which seriously jeopardizes human health. It is a common cause of disability with unclear etiology. Angiogenesis is an important pathological basis of RA, which exacerbates synovitis, leading to the destruction of articular cartilage and bone. However, the optimized target for angiogenesis has not been found yet. Sphingosine-1-phosphate (S1P) has been emerged as a mediator of angiogenesis both in tumor growth and inflammation. S1P is highly expressed in RA synovium, but its role in RA is not clear. In the previous work, we found that S1P-induced RA synovial fibroblasts secreted high level of interleukin-6, which is an important angiogenic factor in RA synovium. We therefore speculate that S1P is an inducer of RA angiogenesis. This project intends to clarify the role of S1P in RA synovial angiogenesis in order to prove this hypothesis. Research on molecular, cellular and whole animal levels will be performed to represent the mechanisms involved in this process. Both animal and cell models of RA as well as angiogenesis model will be utilized to locate the critical target for S1P-S1P receptor signaling system. Our research aims to provide theoretical basis and seek new target point for RA treatment.

类风湿关节炎（RA）是一种严重危害人类健康的自身免疫病，致残率高，机制不详。RA滑膜组织新生血管形成可加剧滑膜炎症反应，导致关节软骨和骨破坏，成为RA发生发展的重要病理基础，然而迄今尚未找到防治滑膜血管新生的最佳作用靶点。1-磷酸鞘氨醇（S1P）是肿瘤和炎症反应中关键的促血管生成分子，在RA关节中表达增加，但具体作用尚不明确。我们在前期工作中发现S1P可诱导RA滑膜成纤维细胞分泌白细胞介素-6，后者是RA滑膜中重要的促血管生成因子，因此我们推测S1P是RA血管新生的诱导剂。为证明该假说，本研究拟在分子、细胞和整体动物水平上研究S1P与滑膜血管新生的关系，通过干扰其激酶-受体途径，探讨关键作用靶点，并通过复制细胞炎症模型和缺氧模型，模拟RA关节腔内环境，探讨S1P途径的信号转导机制，从而为进一步探索RA发病机制奠定理论基础，为寻找新的靶向治疗药物提供实验依据。

类风湿关节炎（RA）是一种发病率高、致残率高的自身免疫病，以持续性滑膜炎症，侵蚀软骨和骨导致关节损伤为特点。新生血管形成是维持与加剧滑膜炎症，导致关节破坏的重要病理基础。近期研究发现1-磷酸鞘氨醇（S1P）是RA滑膜炎症反应的重要信号分子，但尚缺乏其对滑膜血管新生作用的探讨。RA滑膜成纤维细胞（FLS）表达S1P受体（S1PR），S1P和TNF-α通过S1PR影响RA病理进程。本项目分别在体内体外研究S1P及其激酶、受体途径对RA滑膜血管生成的影响。在体外模拟了RA关节腔内环境，干扰S1P/S1PR通路活性，利用芯片发现并筛选出受S1P调控的主要血管增殖细胞因子如VEGF、FGF、MMP9等，利用磷酸化蛋白芯片明确受S1P调控的MAPK信号通路磷酸化蛋白，并通过transwell迁移和matrigel成管试验研究参与S1P促血管生成活性的受体类型和可能的信号转导途径；体内研究则复制了经典RA动物模型（CIA小鼠模型），研究S1P受体和激酶抑制剂对CIA小鼠关节症状、关节评分、整体情况的影响，结果发现S1P受体和激酶抑制剂能有效控制关节炎症反应，抑制滑膜血管增殖，上述结果揭示了S1P/S1PR通路调控RA滑膜新生血管形成的作用，明确有效信号位点，为进一步探索RA发病机制，寻找新的靶向治疗药物奠定理论基础。