类风湿关节炎(RA)成纤维样滑膜细胞(FLS)迁移/侵袭导致关节破坏及患者残疾，现有药物不能阻断此过程，部分患者规律治疗后，病情不缓解或持续关节破坏，属难治性RA。我们预实验发现难治性RA关节局部趋化因子CCL18显著升高，且CCL18在体外能促进RA-FLS的F-肌动蛋白聚合、迁移、侵袭及产生基质金属蛋白酶3(与侵袭软骨相关)，表达谱芯片发现CCL18显著上调RA-FLS中细胞分裂周期蛋白(Cdc)42转录并经验证。目前已知Cdc42-GTP酶通过影响细胞骨架而驱动细胞迁移/侵袭。故我们提出科学假说：CCL18通过激活Cdc42-GTP酶促进RA-FLS迁移、侵袭破坏关节。本项目拟通过体外基因调控及体内动物实验，结合全自动细胞组高内涵定量分析细胞骨架、实时细胞动态分析等技术，阐明CCL18促进RA-FLS迁移及侵袭破坏关节的作用及可能机制，为寻找控制RA关节破坏治疗靶点提供新的理论依据。

Migration and invasion of fibroblast-like synoviocytes (FLS) which cannot be intervened by present therapies lead to persistent joint destruction and disability in rheumatoid arthritis (RA). Some refractory RA patients didn’t reach remission and kept persistent joint destruction even though progressive therapies. Our pre-experiments showed chemokine CCL18 level significantly increased in joints of refractory RA patients; and CCL18 in vitro promoted F-actin polymerization, cellular migration/invasion and production of matrix metalloproteinases which mediated cartilage degradation in RA-FLS. By expression profile microarray chip, we found CCL18 upregulated the transcription of cell division cycle protein 42 (Cdc42) in RA-FLS, which has been verified. It has been known that Cdc42-GTPase promotes cellular migration/invasion through acting on cytoskeleton. To sum up, we propose a hypothesis that CCL18 promote the migration/ invasion of RA-FLS through Cdc42 GTPase. We will perform in vitro gene regulation, in vivo animals experiments, automatic cell array scan with high content screening to analyze cytoskeleton and real time cellular analysis for dynamic curve of cell migration/invasion, in order to illustrate the promoting role and mechanism of CCL18 on migration and invasion of RA-FLS, for therapeutic target to retard joint destruction in RA.