年龄相关性白内障（ARC）的形成与晶状体上皮细胞（LEC）衰老密切相关，但机制未阐明。近期发现环状RNA（circRNA）有很强的基因调控功能并参与细胞衰老。我们研究发现circ-MRE11A和p53/p21信号通路上游ATM基因在ARC患者LEC中表达上调。生物信息学预测circ-MRE11A通过miR-31-5p调控ATM，结合我们前两个国自然课题推测其可能参与ATM转录前（表观遗传）和/或转录后（微小RNA）调控致细胞衰老。申请人拟以人白内障LEC、细胞株、基因敲除斑马鱼、ARC小鼠为三种研究对象。首先在人LEC中明确circ-MRE11A与ATM的关系，再在细胞株中通过FISH、RIP、RNA沉淀和FR-EMSA探明circ-MRE11A调控ATM的机制。最后动物模型眼内注射circ-MRE11A干预质粒，验证延缓ARC的可能。为设计延缓LEC衰老的ARC精准防治提供新的理论基础。

Age-related cataract (ARC) formation is tightly related with cellular senescence of lens epithelial cells (LECs), but the mechanism of intermediated pathways remains to be determined. Recently, studies found the extraordinary function of circular RNAs (circRNAs) in gene regulation and their role in cellular senescence. Our preliminary data showed an upregulation of circ-MRE11A and oxidative damage repair gene ATM that is a gene of upstream of the p53/p21 signaling pathway in LECs of ARC. Bioinformatics analysis indicates circ-MRE11A could regulate ATM expression by hsa-miR-31-5p. Combined with two studies sponsored by The Natural Science Foundation of China, we hypothesize circ-MRE11A is involved in the regulation of ATM epigenetically and post-transcriptionally in the process of LEC senescence, which results the formation of cellular senescence. We will use ARC LECs, cell lines, Zebrafish and ARC mouse model to unveil the relationship between circ-MRE11A and ATM and the molecular mechanisms of circ-MRE11A in cellular senescence and ARC pathogenesis by FISH, RIP, RNA pull down and FR-EMSA. The results would provide a new insight to the disease mechanism and add a novel strategy for ARC precision medicine by targeting circRNAs.