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.