环状RNA-Cdyl通过促进Th17细胞分化参与胶原诱导性关节炎小鼠发病的机制研究

Th17 cells play an important role in the pathogenesis of rheumatoid arthritis(RA), circular RNA is a kind of non coding RNA which can regulate many biological effects of cells. We found that circ-Cdly could regulate the differentiation of mouse Th17 cells in vitro, and affect the transcription of their parental mRNA (Cdyl). Also, the expression of circ-Cdly in CIA mouse was increased. It has been suggested that Cdyl encoded protein may promote the differentiation of Th17 cells. Therefore, we hypothesized that circ-Cdly may influence the differentiation of Th17 cells by regulating the transcription of Cdyl mRNA, and further involved in the pathogenesis of arthritis in CIA mice. In this project, how circ-Cdly regulates the differentiation of Th17 cells by affecting the transcription of Cdyl mRNA will be further studied, and the role of this mechanism during the pathogenesis of arthritis in CIA mice will be explored. In addition, we will analysis relationship between circ-Cdyl with Th17 cells and disease progression in the pathogenesis of rheumatoid arthritis. This project will provide a new theoretical basis for the study of the pathogenesis of RA disease and expected to provide a new strategy for the diagnosis and treatment of RA patients.

Th17细胞在类风湿关节炎（RA）发病过程中发挥重要作用，环状RNA为一种能调控细胞多种生物学效应的非编码RNA。我们发现circ-Cdyl在体外参与调节小鼠Th17细胞分化，同时影响其同源线性mRNA（Cdyl）转录；且circ-Cdyl在胶原诱导性关节炎小鼠（CIA）体内高表达。文献提示Cdyl编码的蛋白可能促进Th17细胞分化。因此，我们推测circ-Cdyl可能通过增强线性Cdyl转录而影响Th17细胞分化，进而参与CIA小鼠关节炎发病。本课题将进一步研究：（1）circ-Cdyl增强线性Cdyl转录的方式，进而阐明circ-Cdly调控Th17细胞分化的机制；（2）circ-Cdly能否通过调控Th17细胞分化参与CIA小鼠关节炎的发病；（3）RA患者体内circ-Cdyl与Th17细胞的关系，从而探索circ-Cdly参与RA发病可能的机制。研究有望为RA的诊治提供新策略。

类风湿关节炎（Rheumatoid arthritis，RA）是一类好发于女性的自身免疫性疾病，不受控制的类风湿关节炎会导致关节损伤，残疾，心血管疾病和其他并发症，影响患者生活质量，严重威胁人类的健康。本项目在小鼠CIA模型以及体外细胞模型中，利用先进的分子生物学方法，明确环状RNA调控Th17细胞分化的新机制。首次证实了circ_cdly通过增强其线性转录本CDYL的表达以及和EZH2的结合，促进Th17细胞分化。此外，干扰circ_cdyl表达的CD4+T细胞能够延缓CIA小鼠关节炎的发病，且减少其体内Th17细胞数目。研究结果为寻找预防、治疗类风湿关节炎的新策略提供了理论基础。