miR-124a靶向PIK3CA调控类风湿关节炎成纤维样滑膜细胞增殖和凋亡及其机制研究

Rheumatoid arthritis(RA) is a chronic autoimmune disease characterized by synovial inflammation and joint destruction. It is currently accepted that the anormality in cell proliferation and apoptosis of RA fibroblast-like synoviocytes(FLS) plays a key role in the synovial inflammation and joint destruction. Our preliminary study revealed that the activation of PI3K/Akt signal pathway is one of important factors responsible for the disregulation of proliferation and apoptosis in RA FLS, although the specific mechanism remains elusive. It was reported recently that microRNA is involved in RA FLS proliferation and apoptosis. Using miRNA chip and bioinformatic analysis, we revealed a downregulated miR-124a expression in RA FLS, and further refered that the target gene of miR-124a may be PIK3CA gene in the PI3K/Akt signal pathway. And thus, our study group plan to dig into how miR-124a involves in RA FLS proliferation, apoptosis and in the PI3K/Akt signal, which will provide a potent theoretical backgroud for the further exploration of RA pathogenesis and the development of new miR-124a-targeted drug and treatment strategies.

类风湿关节炎(RA)是以滑膜炎和关节破坏为特征的慢性自身免疫性疾病，RA成纤维样滑膜细胞（FLS）增殖异常与凋亡障碍是导致滑膜炎及关节破坏的关键因素。申请者前期研究发现：PI3K/Akt通路活化在RA FLS增殖及凋亡障碍中起重要作用，但具体机制不清楚。有研究表明microRNA(miRNA)参与了RA FLS增殖及凋亡过程，项目组使用miRNA芯片及生物信息学分析初步发现：miR-124a在RA FLS中表达下调，其靶基因可能为PI3K/Akt通路PIK3CA基因，提示miR-124a可能是RA FLS增殖异常与凋亡障碍的关键调控因子之一。本项目拟使用细胞及CIA动物模型，采用原位杂交、Northern blot、荧光素酶报告基因、miR转染等技术深入研究miR-124a对RA FLS增殖/凋亡影响及其调控机制，为阐明RA发病机制，设计以miRNA为靶点的新型药物提供实验及理论基础。

类风湿关节炎(RA)是以滑膜炎和关节破坏为特征的慢性自身免疫性疾病，RA成纤维样滑膜细胞（FLS）增殖异常与凋亡障碍是导致滑膜炎及关节破坏的关键因素。申请者研究证实miR-124a可抑制TNF-α诱导的RA FLS增殖、促进凋亡；其主要机制之一是miR-124a靶向PIK3CA基因下调PI3K/Akt信号通路akt,进而影响下游分子bcl/bax的表达； 同时动物实验观察到miR-124a可减少胶原诱导关节炎（CIA）小鼠关节炎症，提示miR-124a激动剂对CIA小鼠有可能的治疗作用。该研究为阐明RA发病机制，设计以miRNA为靶点的新型药物提供实验及理论基础。