Choriocapillaris Protection and Replacement in AMD

描述(申请人提供)：老年性黄斑变性(AMD)是导致失明的主要原因，其特征是视网膜色素上皮-脉络膜毛细血管界面的病理变化。我们最近发现脉络膜毛细血管的缺失与AMD最早的临床症状有关，而血管密度的降低和“幽灵”血管的数量增加与玻璃体和其他RPE下沉积的大小和数量有关。在脉络膜毛细血管水平激活末端补体途径和形成膜攻击复合体(MAC)可能是AMD血管丢失的一个原因。在这项建议中，我们试图确定MAC损伤的脉络膜内皮细胞的分子和细胞反应；识别保护脉络膜内皮细胞免受MAC介导的裂解的小分子；并开发和测试最终替代丢失的内皮细胞的途径。我们预计，这些目标的完成将导致对AMD早期脉络膜保护机制的重要新理解，这可能导致这种致盲疾病的新疗法。

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is a major cause of blindness that is characterized by pathologic changes at the retinal pigment epithelium-choriocapillaris interface. We recently found that vascular loss of the choriocapillaris is relatedto 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. 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 in AMD. In this proposal we seek to identify the molecular and cellular responses of choroidal endothelial cells injured by MAC; to identify small molecules that protect choroidal endothelial cells against MAC-mediated lysis; and to develop and test avenues for the eventual replacement of lost endothelial cells. We anticipate that completion of these aims will result in important new understanding of mechanisms of protecting the choroid in early AMD, which may lead to new therapies for this blinding disease.