Choriocapillaris Protection and Replacement in AMD

摘要 老年性黄斑变性(AMD)是世界范围内导致失明的主要原因，其特点是 视网膜色素上皮-脉络膜毛细血管界面的病理变化。我们最近发现， 脉络膜毛细血管内皮细胞与AMD最早的临床症状有关，并且 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 其他亚RPE矿床。令人信服的证据表明，末端补体途径的激活和 脉络膜毛细血管水平膜攻击复合体(MAC)的形成可能是导致 血管丢失与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 脉络膜内皮细胞到MAC组装；确定是什么使脉络膜内皮细胞 易感MAC攻击；并确定供体细胞CFH基因是否影响整合能力， IPSC来源的脉络膜内皮细胞移植后的功能和寿命。我们预料到 完成本申请中概述的目标将导致对疾病的重要的新理解 病理生理学，这将使我们能够进一步开发专注于保护和替换的治疗方法 AMD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.