成纤维样滑膜细胞（FLS）异常增殖和侵袭是类风湿关节炎（RA）关节破坏进展的关键因素。我们发现溴区蛋白4（BRD4）在RA患者滑膜病变中发挥关键作用，抑制BRD4能控制RA FLS增殖、迁移和侵袭，明显改善CIA小鼠的关节破坏，但BRD4调控RA FLS功能的分子机制仍不清楚。近期发现BRD4通过长链非编码RNA（lncRNA）调节肿瘤细胞生长和侵袭。利用基因芯片筛选，我们发现lncRNA 9194在RA FLS中表达明显高于正常人，下调lncRNA 9194表达显著抑制FLS增殖、迁移和侵袭；抑制BRD4下调lncRNA 9194表达。本课题拟在上述基础上，深入研究lncRNA 9194对RA FLS增殖和侵袭的调控及其机制，明确lncRNA 9194是否介导BRD4调控RA FLS增殖和侵袭，旨在阐明BRD4调控RA滑膜病变的分子机制，进一步揭示lncRNA在RA发病机制中的作用。

Abnormal proliferation and invasion of fibroblast like synoviocytes (FLSs) play a key role in controlling the progress of synovial invasion and joint destruction of rheumatoid arthritis (RA). Our previous studies indicate the critical role of bromodomain protein BRD4 in synovial inflammation, proliferation and invasion, however, the underlying mechanisms of BRD4 inhibition for regulating RA FLSs function is still unclear. In recent years, it has been shown that inhibition of BRD4 suppresses growth and invasion in some kinds of cancer through regulating long noncoding RNA (lncRNA). We have found that expression of lncRNA 9194 is significantly increased in FLSs from RA patients compared with healthy controls. lncRNA 9194 is mainly located in cytoplasm. Inhibition of lncRNA 9194 by specific siRNA suppressed proliferation, migration and invasion of RA FLS. BRD4 inhibition downregulated the expression of lncRNA 9194. Therefore, based on our previous studies, this proposal will be aimed at identifying the role of lncRNA 9194 in regulating proliferation, migration and invasion of RA FLSs. We further search for the “molecular target” that interacts with lncRNA 9194 and regulates FLS function by using bioinformatics analysis, RNA pulldown and RNA immunoprecipitation (IP). We will further determine whether lncRNA is involved in the regulation of BRD4 inhibition in RA FLSs function. We propose to clarify the mechanisms underlying synovial proliferation, invasion and joint destruction of RA in the term of epigenetics, providing the scientific basis for establishment of a novel therapeutic target for RA.