NOX2介导ROS-JNK和PKR-CHOP-TRB3通路在实验性视网膜脱离中调控凋亡的机制研究

项目名称： NOX2介导ROS-JNK和PKR-CHOP-TRB3通路在实验性视网膜脱离中调控凋亡的机制研究

项目编号： No.81500729

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 闫泉

作者单位： 上海交通大学

项目金额： 18万元

中文摘要： 视网膜脱离（RD）是严重影响患者视觉功能的致盲性眼病。前期研究发现，RD中光感受器细胞发生线粒体途径凋亡和内质网应激途径凋亡是视功能损伤的重要因素。然而抑制凋亡信号通路下游分子，仅能部分减少光感受器细胞凋亡。因此寻找凋亡信号上游关键调控靶点，才能更大程度阻断凋亡信号传导。新近发现，NOX2在促进ROS生成诱导线粒体途径凋亡的同时，还可激活PKR放大CHOP信号，促进内质网应激途径凋亡。由此推测NOX2很可能是RD中共同调控线粒体途径凋亡和内质网应激途径凋亡的上游关键信号枢纽。为证实该假设，本课题拟构建RD动物模型及体外光感受器细胞应激模型，采用基因沉默与过表达技术干预NOX2表达水平，通过体内外实验探讨NOX2介导ROS-JNK和PKR-CHOP-TRB3通路在实验性RD中调控光感受器细胞凋亡的作用及机制，为今后寻找RD中凋亡信号拮抗分子，进而重建和修复视功能提供新的理论依据和治疗思路。

中文关键词： 视网膜脱离；凋亡；内质网应激；光感受器细胞；NOX2

英文摘要： Retinal detachment (RD) is a common cause of permanent visual impairment. In previous studies, mitochondrial and endoplasmic reticulum stress-mediated apoptosis has shown to be responsible for photoreceptor loss after RD. However, photoreceptor apoptosis could only be partially suppressed after inhibition of downstream signaling molecules of apoptosis pathway. It indicates that apoptosis signaling transduction could be blocked by intervening upstream regulatory target. NOX2 is nearly found to induce the production of ROS and subsequent mitochondrial apoptosis, and simultaneously amplify CHOP-induced endoplasmic reticulum stress through activating PKR. Based on these findings, we hypothesis that NOX2 plays a key role in regulating mitochondrial and endoplasmic reticulum stress-mediated apoptosis after RD. In order to verify the hypothesis, we will establish rat models of RD and photoreceptor culture and investigate the regulatory mechanism of NOX2-induced ROS-JNK and PRK-CHOP-TRB3 pathways on photoreceptor apoptosis using siRNA and overexpression technology. The complement of this study will provide a new therapeutic target to suppress photoreceptor apoptosis and improve visual function after RD.

英文关键词： Retinal detachment;Apoptosis;Endoplasmic reticulum stress;Photoreceptor;NADPH oxidase 2