ABSTRACT Advanced neovascular age-related macular degeneration (AMD) is characterized by choroidal neovascularization (CNV), in which neovessels originating from the choroid invade the macula. CNV causes permanent central blindness if left untreated and is the most sight-threatening pathology of AMD. The present application will investigate the efficacy and regulatory mechanisms for a new class of CNV therapeutics. We have identified in our preliminary data that ketone bodies suppress CNV and hypothesize that this effect is regulated by macrophage and/or microglia reprogramming, which results in protective inflammation and/or suppression of pathological inflammation. We will refute or validate this hypothesis in three Specific Aims. In Aim 1, we will determine the therapeutic effects of ketone metabolites and their potential synergistic effect with anti-VEGF therapies, the current standard of care for CNV. We will also determine whether the anti-angiogenic effects of ketone metabolites are regulated by direct effects on endothelial cells or ketone-induced immune cell phenotypic changes using co-culture models. In Aim 2, we will identify whether ketone bodies suppress CNV via microglia, macrophages recruited from the circulation, or both. In Aim 3, we will determine the role of the ketone body receptor, G Protein-coupled receptor 109a (Gpr109a) in phenotypic reprogramming of specific immune cell subpopulations.