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，我们试图确定脉络膜内皮细胞损伤的分子和细胞反应。 通过MAC；评估保护脉络膜内皮细胞免受MAC介导的裂解的小分子；以及 目的：建立一种基于自体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产生一个重要的新的 对疾病病理生理学的了解，这将使我们能够进一步开发专注于 保护和替换AMD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.