LOXL1基因多态性与DNA甲基化在新疆维吾尔族剥脱综合征白内障发病过程中的作用机制研究

项目名称： LOXL1基因多态性与DNA甲基化在新疆维吾尔族剥脱综合征白内障发病过程中的作用机制研究

项目编号： No.U1503124

项目类型： 联合基金项目

立项/批准年度： 2016

项目学科： 管理科学

项目作者： 蒋永祥

作者单位： 复旦大学

项目金额： 50万元

中文摘要： 剥脱综合征性白内障（XFSC）新疆维吾尔族人群高发，病因不明，致盲率高，手术效果差。LOXL1基因是其易感基因，但不能解释发病主要特点。本项目组前期研究发现随着XFSC病变程度加深，晶状体前囊膜LOXL1蛋白表达量降低且其基因启动子区DNA甲基化程度明显增加，据此提出“LOXL1基因多态联合DNA甲基化共同促使XFSC发生发展”的假说。拟首先提取XFSC遗传家系及散发病例与对照组患者静脉血DNA，对LOXL1基因外显子、启动子及3'UTR区域进行测序检测基因多态并进行其功能验证；其次分析前囊膜LOXL1基因DNA甲基化程度变化规律，检测其基因表达水平及DNA甲基化抑制剂Zebularine的干预效果；并通过晶状体上皮细胞基因敲减检测LOX L1基因表达及产生弹性蛋白能力、细胞活性与抗氧化能力改变，从而阐明LOXL1基因遗传学与表观遗传学改变在XFSC发病中的作用，为进一步临床干预打下基础。

中文关键词： 剥脱综合征；白内障；LOXL1基因；基因多态；DNA甲基化

英文摘要： Exfoliation syndrome combined cataract (XFSC)，whose prevalence varies greatly among ethnic groups and exact cause remains unknown, leads to a high blindness rate. Uygur population in Xinjiang is more susceptible to this disease than other ethnic groups. Although LOXL1 gene has been confirmed as a susceptibility gene, it can not explain the main features of XFSC onset. Our research group has verified that, with the progression of XFSC, expression of LOXL1 protein was down-regulated in the lens capsular membrane, along with a remarkable increase of methylation level in corresponding genetic promoter region. As a basis of preliminary studies, we proposed the hypothesis that LOXL1 gene polymorphism leads to XFSC together with DNA methylation. In this study, venous blood and anterior capsular membrane of XFSC and control group were obtained to extract DNA. Sequencing exon of LOXL1 gene, promoter and 3 'UTR region to detect gene polymorphism and to verify its function. Furthermore, to put our hypothesis to the proof, we analyze the expression of LOXL1 gene, elastin, the proliferation or apoptosis and the function of antioxidation of lens epithelial cells by LOXL1 RNA interference in Vitro. Our aim is to study the relationship between XFSC and the LOXL1 gene polymorphism together with DNA methylation during XFSC occurence and development, to clarify the important role of genetics and epigenetic changes of LOXL1 gene in the pathogenesis of XFSC. It may provide a theoretical basis for early intervention and treatment on XFSC.

英文关键词： exfoliation syndrome;cataract;LOXL1 gene;gene polymorphisms;DNA methylation