长链非编码RNA H19在类风湿关节炎成纤维样滑膜细胞促炎中的作用及调控机制

Long noncoding RNA H19(lncRNA H19) is significantly higher expressed in Rheumatoid Arthritis(RA) fibroblast-like synoviocytes (FLS). However it is unclear about the relationship between lncRNA H19 and FLS pro-inflammatory, and it is unknown the regulation mechanisms of lncRNA H19. Our preliminary study for the first time showed that lncRNA H19 expression was closely related FLS proliferation and inflammatory factor production, and nuclear receptor LXR could significantly repress lncRNA H19 expression and inhibits its transcriptional activity. Furthermore, lncRNA H19 could significantly regulates the expression of mir-124a and its target genes. In the present study, we will do the following researches: 1) to identify the molecular mechanism of LXR regulates lncRNA H19 expression, and to confirm for the first time that lncRNA H19 is a novel target gene of LXR; 2) to clarify the molecular mechanism of lncRNA H19 regulates mir-124a expression, which will reveal the existence of lncRNA H19→mir-124a pathway in FLS; 3) to reveal that suppression of lncRNA H19→mir-124a pathway is a novel mechanism in LXR-mediated anti-inflammatory fuction in RA. Moreover, we will elucidate the significance of the novel mechanism in LXR-mediated anti-inflammatory effects. The anticipated results of the present study may provide novel helpful information for detailed revealing the regulation mechanisms of lncRNA H19, and may pave a way for designing novel strategy to the prevention and treatment of RA based on the novel pathway.

长链非编码RNA H19(lncRNA H19)在类风湿关节炎(RA)成纤维样滑膜细胞(FLS)中过表达，但其在FLS促炎过程中的作用及表达调控机制尚不清楚。本项目在率先发现“lncRNA H19与FLS增殖及促炎细胞因子产生密切相关；抗炎核受体LXR可抑制lncRNA H19表达；lncRNA H19能调控mir-124a及其靶基因表达”的基础上，拟详细解析lncRNA H19受LXR抑制的分子机制，明确lncRNA H19是LXR的新靶分子；并阐明lncRNA H19调控mir-124a的分子机制，揭示存在“lncRNA H19→mir-124a通路”；进而经体内外实验，明确LXR作用于“lncRNA H19→mir-124a通路”是其抗炎新机制，阐明该通路在LXR抗炎中的重要性，以期为全面揭示lncRNA H19表达调控机制积累新资料，乃至为探索针对该通路的RA防治新策略提供科学依据

长链非编码RNA H19(lncRNA H19)在类风湿关节炎(RA)成纤维样滑膜细胞(FLS)中过表达，但其在FLS促炎过程中的作用及表达调控机制尚不清楚。. 本项目在前期研究基础上，① 探索了lncRNA H19是否为LXR直接调控的新靶分子及其调节lncRNA H19表达的分子机制；② 研究了lncRNA H19下调mir-124a及其靶分子的分子机制；③ 证实了活化LXR而抑制lncRNA H19表达是LXR在RA中抗炎的一个新机制；④ 在RA动物模型中，明确了活化LXR作用于“lncRNA H19→mir-124a通路”在体内抗炎功能中的重要性。. 结果表明：① 过表达lncRNA H19明显促进成纤维样滑膜细胞增殖及促炎细胞因子产生；沉默lncRNA H19后，显著抑制细胞增殖及促炎细胞因子产生，RA模型中lncRNA-H19的局部敲低减弱了体内CIA的严重程度。② LXR激动剂通过下调lncRNA-H19的表达来抑制MH7A细胞的增殖。③ 过表达lncRNA H19能抑制mir-124a表达，且可上调mir-124a靶基因表达；在lncRNA H19序列中包含mir-124a的结合位点；miR-124a介导ln7RNA-H19在MH7A细胞中下调CDK2和MCP-1。④ LXR激动剂抑制MH7A细胞中lncRNA H19介导的miR-124a-CDK2/MCP-1信号通路。. 该研究明确llncRNA H19是LXR的新靶分子；并阐明了lncRNA H19调控mir-124a的分子机制，揭示存在“lncRNA H19→mir-124a通路”；经体内外实验，明确了LXR作用于“lncRNA H19→mir-124a通路”是其抗炎新机制，阐明了该通路在LXR抗炎中的重要性，为全面揭示lncRNA H19表达调控机制积累了新的资料，乃至为探索针对该通路的RA防治新策略提供了科学依据。