LncRNA-ENST00000483588/miR-326/SHH轴对RA成纤维样滑膜细胞增殖和侵袭的调控及其机制研究

Fibroblast-like synoviocytes (FLS) are the major effector cells that lead to rheumatoid arthritis (RA) synovitis and joint destruction. Our previous studies suggest that SHH signaling pathway was abnormally activated in RA and involved in the over-proliferation and migration of RA-FLS. Moreover, the expression level of LncRNA-ENST00000483588 in RA-FLS was up-regulated. Via bioinformatics analysis, we hypothesize that LncRNA-ENST00000483588 may be involved in the SHH pathway signal transduction by interaction with miR-326 and/or other miRNAs. In current study, we will adopt a combination of in vivo and in vitro experiments to explore the role of LncRNA-ENST00000483588 on the genetic regulation mechanism of SHH pathway in RA, ①Study the effects of ENST00000483588 on synovial inflammation and joint destruction of RA; and ②Investigate the molecular mechanism of ENST00000483588 in SHH-regulated synovial lesions and joint destruction of RA. Our study will help to reveal the genetic regulation mechanism of SHH pathway in RA and provide experimental evidence for developing new drugs for RA.

成纤维样滑膜细胞（FLS）是类风湿关节炎（RA）滑膜炎和关节破坏的主要效应细胞。我们前期研究发现，SHH通路在RA中存在异常活化，参与RA-FLS过度增殖、迁移等过程，RA-FLS的LncRNA-ENST00000483588表达上调。经文献阅读与生物信息学分析，预测LncRNA-ENST00000483588可能通过作用于miR-326和/或其他miRNAs参与SHH通路信号转导。为探索ENST00000483588对RA病变中SHH通路的基因调控作用，拟采用体内和体外实验相结合的模式，①探索ENST00000483588对RA关节滑膜炎症和关节破坏的影响；②探索ENST00000483588在SHH信号通路调控RA滑膜病变和关节破坏中的分子机制。本项目的完成将利于进一步阐明SHH通路参与调控RA滑膜病变的分子作用机制，为开发治疗RA的新药提供实验依据。

成纤维样滑膜细胞（FLS）是类风湿关节炎（RA）滑膜炎和关节破坏的主要效应细胞。我们前期研究发现，SHH通路在RA中存在异常活化，参与RA-FLS过度增殖、迁移等过程，RA-FLS的LncRNA-ENST00000483588表达上调。为探索ENST00000483588对RA病变中SHH通路的基因调控作用，拟采用体内和体外实验相结合的模式，①探索ENST00000483588对RA关节滑膜炎症和关节破坏的影响；②探索ENST00000483588在SHH信号通路调控RA滑膜病变和关节破坏中的分子机制。本研究至目前 1）阐明 SHH 基因上调对 RA动物模型关节滑膜和软骨病变的影响，2) 揭示 p-38/MAPK、Rho/ROCK、 JNK信号通路在 SHH 调控 RA-FLS 细胞增殖、迁移及其下游相关生物学效应过程中所扮演的角色的研究目标。3）阐明长链非编码核仁小分子 RNA 宿主基因 1 对类风湿关节炎成纤维样滑膜细胞增殖的影响，并设计完成针对SMO的siRNA核酸药物。未完成部分：未能完成 ENST00000483588 过表达/沉默对调控 DBA/1 关节炎小鼠模型关节破坏的影响本项目的完成将利于进一步阐明SHH通路参与调控RA滑膜病变的分子作用机制，为开发治疗RA的新药提供实验依据。