FTO和ALKBH5介导的m6A去甲基化对RA成纤维样滑膜细胞迁移和侵袭的调控及机制

成纤维样滑膜细胞（FLS）异常迁移和侵袭是类风湿关节炎（RA）滑膜病变和关节破坏持续进展的关键因素。N6-甲基腺嘌呤（m6A）异常修饰在肿瘤生长和侵袭中发挥重要作用，但其在RA滑膜病变中的作用未见报道。我们前期发现m6A水平在RA滑膜组织及FLS中均明显下调；m6A去甲基化酶FTO和ALKBH5表达则明显上调，且滑膜组织中两者表达水平均与疾病活动度呈相关性；敲低RA FLS中FTO或ALKBH5可上调m6A水平并抑制细胞迁移和侵袭。本课题拟在现有工作基础上，进一步明确FTO及ALKBH5介导的m6A去甲基化对RA FLS迁移和侵袭的调控作用，并利用生物信息学、m6A-seq、RNA-seq等技术寻找FTO和/或ALKBH5结合并能调控FLS功能的“目标RNA”，以阐明m6A去甲基化调控RA FLS功能的分子机制，旨在揭示RA滑膜侵袭和关节破坏的表观遗传新机制，有望为RA治疗提供新靶点。

Abnormal migration and invasion of fibroblast like synoviocytes (FLS) play a key role in the progression of synovial lesion and joint destruction of rheumatoid arthritis (RA). It has been demonstrated that N6-methyladenosine (m6A) modification abnormality is involved in the modulation of growth and invasion in several types of cancer, but its role in the pathogenesis of RA has not been reported. We found that the m6A level is significantly decreased in synovium and FLS from RA patients, whereas m6A erasers FTO and ALKBH5 are increased. The expression of FTO and ALKBH5 in RA synovium has correlated with diseases activity scores. Knockdown of FTO or ALKBH5 by lentivirus infection upregulated the m6A level and suppressed the migration and invasion of RA FLS. Therefore, based on our previous studies, this proposal will be aimed at identifying the role of m6A modification mediated by FTO and ALKBH5 in regulating migration and invasion of RA FLS. We further search for the “molecular target” of m6A modification that mediated by FTO or ALKBH5 and regulates FLS function and investigate the mechanism of m6A erasers FTO and ALKBH5 on the target mRNA transcripts by using bioinformatics analysis, m6A-seq, and RNA-seq. By revealing the mechanisms underlying synovial inflammation and joint destruction of RA in the term of epigenetics, our study may provide a novel potential therapeutic target for RA.