miR-146a/Fas调控生发中心反应及参与类风湿关节炎发病的机制研究

项目名称： miR-146a/Fas调控生发中心反应及参与类风湿关节炎发病的机制研究

项目编号： No.81471609

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 李景怡

作者单位： 中国人民解放军第三军医大学

项目金额： 75万元

中文摘要： 类风湿关节炎（RA）患者淋巴结和滑膜异常的生发中心（GC）反应，分泌大量高亲和力的自身抗体，是导致炎症持续存在和慢性化的重要因素。课题组前期研究发现RA滑液CD4+ T细胞和B细胞均高表达miR-146a，miR-146a转基因小鼠呈现生发中心增多、GCB细胞明显增加的特征，并鉴定Fas是miR-146a在GCB细胞中特异的靶基因，提示miR-146a/Fas可能调控了生发中心反应，并最终参与了RA中自身抗体的形成。为证实这一假说，我们拟开展如下研究：以转基因小鼠为模型，分析miR-146a/Fas调节GC反应的特点及机制；以K/BxN小鼠和RA病人为研究对象，探讨miR-146a/Fas对GC反应和GCB功能的影响，并分析调节的分子网络，进一步阐明miR146a/Fas调控GC反应并参与RA发病的分子机制。本研究的完成有助于深入理解RA的免疫病理机制，并为RA的治疗策略提供了新的线索。

中文关键词： miR-146a；Fas；生发中心反应；类风湿关节炎；发病机制

英文摘要： A large amount of autoantibodies production depend on germinal center (GC) response in autoimmune pathogenesis. Altered GC response has been revealed in lymph nodes and synovium in rheumatoid arthritis(RA) patients, which is critical for sustained progress of this chronic disease.Our pilot studies have found that high levels of miR-146a in CD4+ T cells and B cells purified from synovial fluid of RA. Moreover,we found incresed sizes of GCs and more GC B cells in spleen and lymph nodes in miR-146a transgenic mice. We also identified that Fas is the specific target gene of miR-146a in GC B cells. Based on these findings, we hypothesize that miR-146a/Fas maybe regulate GC response and finally involve in the secretion of autoantibody in RA.In this study,we will determine the molecular mechanisms underlying miR-146a-mediated GC formation,GC B cell differentiation and function. Next, Using a mouse K/BxN model with autoimmune arthritis, we will investigate whether and how GC B cells with miR-146a-overexpressing contribute to GC response and autoimune progression. Furthermore, we will examine the role of miR-146a/Fas in modulating GC B cell functions from RA patients and normal subjects and elucidate the molecular mechanisms involve in synovial inflammation in RA. Together, our proposed studies will provide further insight in understanding autoimmune progression and may facilitate the development of new treatment strategy for RA.

英文关键词： miR-146a;Fas;germinal center response;rheumatoid arthritis;pathogenesis