年龄相关性黄斑变性光感受器细胞神经保护的分子机制研究

视网膜年龄相关性黄斑变性最终将导致视网膜光感受器细胞的不可逆死亡。由氧应激反应等因素所致视网膜光感受器细胞内钙离子浓度升高,会激活线粒体内源性凋亡途径，导致光感受器凋亡。我们将从神经保护角度出发，提出稳定光感受器细胞内钙的一条途径，即通过抑制光感受器在病理状态下的钙离子正反馈增高效应，减少钙超载所致的细胞凋亡。前期工作中我们已验证了光感受器中有钙正反馈通道RyR的表达，电生理实验的初步结果表明N-酰基乙醇胺（NAE）对RyR有抑制作用，减少钙的正反馈。我们已经在离体实验上检测到NAE对光感受器细胞在氧应激条件下有保护作用，并检验到NAE抑制线粒体因氧化应激钙过载所导致的崩解，阻碍了内源性的线粒体凋亡途径。将通过在体的行为学实验观察NAE对AMD模型转基因小鼠的视功能保护作用。本项目中提出针对视网膜的光感受器神经保护途径将为AMD的治疗提供新的思路。

Age-related macular degenation (AMD) leads to retinal photoreceptors apotosis and cause blindness in the aged people. Oxidative stress was considered to be an important and also indepentent risk factor for AMD development, due to pathylogical calcium influx caused photoreceptor appotosis. In this project, we propose to stablize intracellualer calcium level by blocking mitochochia calcium-induced-calcium-influx mechanism to reduce apoptosis and save vision. In our preliminary data, we found that NAE could block calcium-induced-calcium-channel RyR during pathological oxiadation,and also protect mitochondia damage as well as photoreceptors damage during oxidation insult. Hereby in this project, we will test our hypothesis that NAE has neuroprotective effect due to control calcium overload during oxidative stress, by using eletrophysiology, immuonohistochemistry, biochemitry, imaging and behavior study.