自噬在年龄相关性黄斑变性发生发展中的作用机制研究

项目名称： 自噬在年龄相关性黄斑变性发生发展中的作用机制研究

项目编号： No.81470649

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 黄旅珍

作者单位： 北京大学

项目金额： 73万元

中文摘要： 自噬对维持细胞稳态意义重大，是清除衰老细胞器和氧化损伤的主要机制之一。其功能随年龄增长而减弱。研究发现自噬在衰老、神经退行性疾病、免疫和炎症感染中具有重要作用，而年龄相关性黄斑变性（AMD）本质是一种与衰老相关的多因素神经退行性疾病。炎症小体与其发病密切相关。视网膜色素上皮细胞（RPE）的氧化损伤在其发生发展中也具有关键作用。研究证实自噬蛋白LC3表达于衰老的视网膜尤其是RPE和感光细胞中；自噬功能障碍与AMD发生发展有关，但其调控AMD的机制未明。本课题预实验发现，RPE氧化损伤时LC3-II集聚增加。本课题拟利用RPE细胞系、原代RPE细胞以及干性和湿性AMD动物模型，通过自噬诱导剂/抑制剂、基因过表达/敲减方法，围绕线粒体损伤、炎症小体、血管生成促进/抑制因子表达、自噬相关信号通路及RPE细胞功能变化，明确自噬与AMD发生发展的时相关系，为AMD的发病机制及其作用靶点研究提供依据。

中文关键词： 视网膜色素上皮细胞；年龄相关性黄斑变性；自噬；氧化应激

英文摘要： Autophagy plays a significant role in maintaining cellular homeostasis and it is one of the major mechanisms for clearing aging organelles and oxidative damage.Its function decreases with age.Studies found that autophagy played an important role in aging,neurogenerative diseases,immune and inflammatory infection.Age-related macular degeneration actually is a multifactorial neurodegenerative disease associated with aging. Inflammasome is closely related to its onset. Retinal pigment epithelium(RPE) oxidative damage play a crucial role in the development of AMD.Several studies have verified the expression of autophagy protein LC3 in tha aging retina,especially in the RPE layer and photoreceptor cells;autophagy dysfunction related with the development of AMD,however, the regulation mechanisms between autohphagy and AMD is unclear.Our previous study validated that LC3 was elevated after oxidative stress in RPE.RPE cell lines,primary RPE,dry and wet AMD models were used in this study.Autophagy inducer/inhibitor,gene overexpression/gene konck down method were used to study the behavior changes of RPE；the alteration of pro-/anti-angiogenesis factors, mitochondrial damage,inflammasome and autophagy pathway were evaluated to identify the relationship between autophagy and AMD.This study will provide a basis for the pathogenesis anf prevention of AMD.

英文关键词： retinal epithelial cell;age-related macular degeneration;autophagy;oxidative stress