PROJECT SUMMARY/ABSTRACT Age-related macular degeneration (AMD) is the leading cause of blindness among older adults in the developed world. Recent studies provide strong evidence supporting the hypothesis that mitochondrial (Mt) defects in the retinal pigmented epithelium (RPE) contribute to the pathogenesis of AMD. This study will focus on samples from eyebank donors and AMD patients harboring the AMD risk SNP (rs1061170; T to C conversion; amino acid change Y402H) for complement factor H (CFH) since members of this group have significantly more RPE MtDNA damage and display genotype-specific Mt defects in the RPE. Therefore, this genetically defined group may benefit from treatments that protect the mitochondria. Studies in this application will use our primary RPE and induced pluripotent stem cell (iPSC)-derived RPE cultured from individuals with AMD harboring the CFH CC risk alleles, to investigate disease mechanisms and response to drugs that protect or enhance Mt function. Our experimental system is unique in that all donors are phenotyped for disease severity and also genotyped for the AMD CFH risk allele. Aim 1 will test the hypothesis that Mt dysfunction and susceptibility to oxidative stress in primary and iPSC-derived RPE harboring the CC risk alleles are genotype-specific. Aim 2 will test the hypothesis that compounds that enhance Mt activity will preserve RPE cell function and prevent cell death. We will use iPSC-RPE to test the prediction that cells harboring the CC risk allele require different, allele-specific drug combinations to preserve Mt function and prevent RPE cell death compared with cells lacking the risk allele. We will utilize iPSC-RPE from CFH CC and CFH TT donors to determine the optimal cell-protective drug combinations and then test these in the RPE-specific sod2 conditional KO that has Mt and RPE defects. If our prediction is correct, the optimum combination of drugs from the in vitro experiments will protect the retina in the RPE-specific sod2 conditional KO mouse and maintain RPE cell integrity. Aim 3 is translational. We will test the response of iPSC-RPE generated from conjunctival biopsies from living AMD patients harboring the CFH CC risk allele to the optimal drug combinations that improve Mt function. In summary, these studies will define differences in RPE Mt defects, response to oxidative stress and to drugs that improve Mt function, between cells from patients with the CFH CC AMD risk allele and from patients with the TT protective allele. Results from these studies may lead to development of therapies to prevent AMD by targeting the primary defect in a genetically defined population of AMD patients and may also lead to “personalized medicine” for treating AMD since our method for producing patient-specific iPSC-RPE can be readily translated to patients with AMD.