Choriocapillaris Protection and Replacement in AMD

摘要 年龄相关性黄斑变性（AMD）是全球失明的主要原因，其特征是 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下的沉积物。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。在这项建议中，我们试图确定分子和细胞的反应， 脉络膜内皮细胞的MAC组装;以确定是什么使脉络膜内皮细胞 对MAC攻击敏感;以及为了确定供体细胞CFH基因型是否对整合能力有影响， 移植后iPSC衍生的脉络膜内皮细胞的功能和寿命。我们预计 完成本申请中概述的目标将导致对疾病的重要新理解 病理生理学，这将使我们能够进一步开发治疗，重点是保护和取代 AMD中的血管受损。

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 sub-RPE 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 to MAC assembly; to determine what makes choroidal endothelial cells susceptible to MAC attack; and to determine if donor cell CFH genotype has an impact on integrative capacity, function and longevity of iPSC-derived choroidal endothelial cells following transplantation. 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.