PROJECT SUMMARY Age-related macular degeneration (AMD) is one of the leading causes of irreversible visual dysfunction in older individuals in developed countries, resulting in loss of productivity, independence, and quality of life, as well as tremendous healthcare and economic burden. Visual dysfunction in AMD patients could be in the form of ‘‘dry’’ AMD or ‘‘wet’’ AMD or both. While some treatments are available for wet-AMD, but there is no effective treatment for geographic atrophy (GA), the advanced form of dry-AMD. Oxidative stress-induced cellular changes play a significant role in the loss of macular RPE and photoreceptors in dry-AMD. Treatments involving local and sustained delivery of molecules or genes to counteract oxidative stress-induced cellular changes could prevent RPE atrophy. Systemic or retinal delivery EPO-R76E, a modified form of EPO (with reduced erythropoietic activity) improved the function of ganglion cells and photoreceptors cells in the retina. Because of its effect in preventing cell death due to induction oxidative stress, we are especially interested in investigating the precise mechanism(s) of how RPE specific EPO-R76E interacts with other retinal cells and influences aberrant molecular pathways in controlling dry-AMD phenotype. We will interrogate the impact of EPO-R76E using two different animal models showing AMD pathology; one is associated with induction of RPE oxidative stress, and the other due to complement dysregulation. We will use recombinant adeno-associated virus (AAV) with serotype 1 to achieve sustained expression of EPO-R76E and deliver to mice eye via subretinal injection. Our first aim will test molecular mechanisms of the retinal protection by EPO-R76E using proteomics analyses of pathways and cell- specific transcriptional approaches in a mouse model of dry-AMD. Our second aim will test whether sustained expression of EPO-R76E ameliorates dry AMD phenotypes in animal models and interrogate how late in the course of retinal degeneration EPO-R76E will be effective in preventing disease symptoms. Our research will elucidate the role of EPO signaling in RPE function, retinal health, and the approach for preventive or therapeutic intervention of dry-AMD. These studies will identify novel molecular pathways for manipulating the retina and provide a new direction for managing dry-AMD.