Choriocapillaris protection and replacement in AMD

摘要 视网膜相关性黄斑变性（AMD）是全世界失明的主要原因，其特征在于： 视网膜色素上皮-脉络膜毛细血管界面的病理改变。我们最近发现， 脉络膜毛细血管内皮细胞与AMD的最早临床体征有关， 血管密度和“幽灵”血管数量的增加与玻璃疣的大小和数量有关， 其他RPE亚层沉积物。令人信服的证据表明，激活终末补体途径和 在脉络膜毛细血管水平形成膜攻击复合体（MAC）可能是导致 血管损失和AMD发病机制。 在这个建议中，我们试图确定脉络膜内皮细胞损伤的分子和细胞反应， 评估保护脉络膜内皮细胞免受MAC介导的溶解的小分子;以及 开发基于自体iPSC的脉络膜内皮细胞替代方法。 我们预计，完成本申请中概述的目标将导致一个重要的新的 了解疾病的病理生理学，这将使我们能够进一步开发治疗重点， 保护和替换AMD中受损的血管。

Abstract Age-related macular degeneration (AMD) is a major cause of blindness worldwide that is characterized by pathologic changes at the retinal pigment epithelium-choriocapillaris interface. We recently found that loss of endothelial cells of the choriocapillaris is related to the earliest clinical signs of AMD, and that a reduced vascular density and increased number of “ghost” vessels are related to the size and number of drusen and other subRPE deposits. Compelling evidence suggest that activation of the terminal complement pathway and formation of the membrane attack complex (MAC) at the level of the choriocapillaris is a likely cause of vascular loss and AMD pathogenesis. In this proposal we seek to identify the molecular and cellular responses of choroidal endothelial cells injured by MAC; to evaluate small molecules that protect choroidal endothelial cells against MAC-mediated lysis; and to develop an autologous iPSC based choroidal endothelial cell replacement approach. We anticipate that completion of the aims outlined in this application will result in an important new understanding of disease pathophysiology, which will allow us to further develop treatments focused on protecting and replacing damaged blood vessels in AMD.