先天性白内障是第一大儿童致盲性眼病。目前认为氧化损伤、晶体蛋白结构异常、晶体蛋白连接异常等几个主要的因素交织在一起贯穿其整个发病过程，但其发病机制至今尚未完全明了。本课题组前期研究证实，在CRYAA（G98R）突变的晶状体上皮细胞中，αA-crystallin可以异常聚集在内质网中导致内质网应激。全基因谱分析也发现Keap1mRNA呈高表达状态。可能导致Keap1-Nrf2抗氧化信号通路的失活参与白内障发生。更重要的是，我们发现Keap1基因启动子区域呈低甲基化状态，且在加入ROS清除剂后，其甲基化状态升高。这提示了一个全新机制—keap1启动子甲基化修饰可能与细胞内质网应激有关。在本研究中，我们将探讨CRYAA（G98R）突变的晶状体上皮细胞中内质网应激所致Keap1基因的启动子区域低甲基化的分子机制，进而探讨其在先天性白内障发病机制中的作用，有望为先天性白内障的治疗提供新的思路和途径。

Congenital cataract is the leading cause of blindness during childhood, the pathogenic mechanisms remain incompletely understood. Oxidative stress, lens crytallin proteins misfolding and abnormal in lens protein-protein interaction play the central role in cataract entire pathogenesis. .Preliminary study showed the aggregated G98R αA-crystallin was mis-localized in endoplasmic reticulum (ER) and induced ER stress in lens epithelial cells harboring CRYAA G98R mutant. Whole gene expression analysis found that the elevated Keap1 mRNA level which involved in congenital cataract pathogenesis through inhibiting Keap1/Nrf2 antioxidant protection. Subsequently, we found the Keap1 promoter DNA hypo-mythelation in mutant cells. Importantly, Demythelation can be rescued by ROS scavenger. This suggested that Keap1 promoter demethylation may caused by the elevated ER stress. In this proposal, we try to explore the mechanism that Keap1 DNA promoter mythelation induced by ER stress in G98R CRYAA mutant lens epithelial cells. Our reseach will provide a new insight of the congenital cataract pathogenesis, and a noval approach for the treatment of congenital cataract.