早期AMD视网膜Aβ毒性作用与血视网膜外屏障P-糖蛋白关系的研究

项目名称： 早期AMD视网膜Aβ毒性作用与血视网膜外屏障P-糖蛋白关系的研究

项目编号： No.81200709

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学二处

项目作者： 张跃红

作者单位： 广州医科大学

项目金额： 23万元

中文摘要： 年龄相关性黄斑变性（AMD）发病机制仍不清楚，而早期AMD视网膜β淀粉样蛋白（Aβ）增高和损害的证据日益增多。已报道血视网膜外屏障P-糖蛋白信号介导机制，初步发现低浓度Aβ可抑制视网膜色素上皮细胞P-糖蛋白表达与活性。借鉴阿尔茨海默氏病的Aβ转运清除学说，推测血视网膜外屏障P-糖蛋白是早期AMD视网膜Aβ增高与损伤的干预靶点。拟继续采用已有血视网膜外屏障模型，完善Aβ抑制P-糖蛋白表达与活性的研究；随后，通过活化和抑制P-糖蛋白信号通路，观察低浓度Aβ玻璃腔注射对小鼠视网膜Aβ含量、外排、视网膜电图和凋亡等的影响；最后采用阿尔茨海默氏病转基因小鼠模型，调节P-糖蛋白信号通路，全面观察视网膜Aβ外排、视网膜电图和凋亡等的改变，进一步验证假说。可望初步明确血视网膜外屏障P-糖蛋白信号通路是否参与早期AMD视网膜的Aβ增高与损伤。

中文关键词： 老年黄斑变性；视网膜色素上皮细胞；淀粉样变性；血视网膜屏障；

英文摘要： The pathogenesis of age-related macular degeneration (AMD) remains unclear and no effective treatment available. It is increasingly clear that the deposits of amyloid beta possibly contribute to the damage of retina in the early stage of AMD. We have reported that signaling pathways of p-glycoprotein located in the outer blood-retinal barrier involved in diabetic retinopathy in vitro. Recently,in preliminary experiments, we found that amyloid bata in low concentration can inhibit the expression and activity of p-glycoprotein both in fresh retinal pigment endothelium cells from na?ve mice and human retinal pigment endothelium cell line D407. Therefore, based on the amyloid beta transport clearance theory of Alzheimer's disease, we now speculate that p-glycoprotein in the outer blood-retinal barrier is a therapeutical target for reducing amyloid beta deposit and attenuating its neurotoxicity in the retina of early AMD. First, using our established in vitro blood-retinal barrier models, we will carry on our investigation in regulatory mechanism of p-glycoprotein mediated amyloid beta increasing and neurotoxicity. Second, we will adjust the p-glycoprotein signaling pathway to assess the role of p-glycoprotein in na?ve mice with intravitreous injection of amyloid beta in low concentrations. Finally, using Tg2576 tran

英文关键词： age related macular degeneration；retinal pigment endothelium；amyloid beta；blood-retinal barrier；