lncRNA-RAAT募集PGC1β促进类风湿关节炎成纤维样滑膜细胞迁移和侵袭的机制研究

成纤维样滑膜细胞（FLS）迁移和侵袭是类风湿关节炎（RA）关节破坏的关键环节，但现有药物不能阻断。我们前期发现转录因子PGC1β可促进RA-FLS迁移和侵袭及基质金属蛋白酶（MMP）3和9表达，但它如何实现靶基因特异性定位及调控尚不清楚。新近报道长链非编码RNA（lncRNA）可特异性募集转录因子到靶基因启动子区域调控转录。我们预实验发现lncRNA-RAAT在RA-FLS中高表达，与关节破坏程度正相关，促进RA-FLS迁移和侵袭，可与PGC1β结合。由此我们提出假说：高表达的lncRNA-RAAT募集PGC1β上调MMPs等靶基因表达从而促进RA-FLS迁移和侵袭，导致关节破坏。本项目拟进一步采用体内外功能学实验、RNA免疫共沉淀、系列缺失和竞争性结合等技术，阐明lncRNA-RAAT调控RA-FLS迁移和侵袭的作用及机制，通过与临床结局相关分析明确其临床意义，为RA精准治疗提供新靶点。

Migration and invasion of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) are critical for inflammation and joint destruction which cannot be intervened by current therapy. Our previous study showed that peroxisome proliferator-activated receptor gamma coactivator (PGC) 1β, a transcription factor, could promote migration and invasion of RA-FLS as well as the expression of matrix metalloproteinase (MMP) 3 and 9. But how PGC1β achieving the specific location and regulation on target genes remains unknown. Emerging evidence shows that long non-coding RNA (lncRNA) regulates transcription by recruiting transcription factors to the promoter of target genes. Our preliminary experiments showed that elevated lncRNA-RAAT in RA-FLS was positively correlated with joint damage and promoted migration and invasion of RA-FLS. What was more, we identified that lncRNA-RAAT could bind to PGC1β. Therefore, our hypothesis is that elevated lncRNA-RAAT in RA-FLS can promote migration and invasion of RA-FLS by recruiting PGC1β which can up-regulate the expression of target genes such as MMPs. In this project, we plan to perform RA-FLS functional experiments in vivo and in vitro, RNA immune coprecipitation, segments deletion, competitive binding analysis and the correlation analysis of clinical outcomes, in order to elucidate the function and mechanism of lncRNA-RAAT in migration and invasion of RA-FLS, and clarify the clinical significance of lncRNA-RAAT in RA which might be a potential therapeutic target for the precise treatment of RA.