Project Summary Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy, caused by >71 mutations that primarily cause rod photoreceptor death. Cone death always follows rod death and starts after the end of major rod death phase regardless of the underlying rod specific gene mutations. Accumulation evidence have shown that cone death in RP is due to glucose starvation. There is a knowledge gap in understanding cellular metabolism in cone and “metabolic coupling” between cone and RPE in RP. Our long-term goal is to prevent blindness in RP due to cone death. Our overall objective is to define how cones and RPE are metabolically coupled and to test potential therapies for RP that are designed to restore this relationship. Our central hypothesis is that reprogramming cone and RPE metabolism can promote cone survival in RP independently of the underlying rod-specific gene mutations. To test this hypothesis, we propose three specific aims. In Aim 1, we will use a cone-specific conditional allele to enhance glycolysis or OXPHOS in cone cells and then determine the effects on cone survival and function in RP mouse models. In Aim 2, we will use an RPE-specific conditional allele to enhance or suppress OXPHOS in RPE and determine the effects on photoreceptor function in RP mouse models. The results from Aim 1 & 2 will elucidate the role of glycolysis and OXPOHS in Cone and RPE cells in mouse model of RP. In Aim 3, we will use virus gene therapy to test therapeutic value of reprogramming cone and RPE metabolisms in 2 preclinical models of RP. Impact: it will address this knowledge gap in cone metabolism and the role of OXPHOS in RPE biology in degenerated retina, which will greatly advance our understanding of the metabolic coupling between cones and the RPE and may provide opportunities for preclinical gene-therapy interventions to prevent cone death or delay photoreceptor degeneration through reprogramming of cellular metabolism. This proposal is innovative because it: 1) will use innovative inducible cell-specific Cre drivers to address previously unanswered questions that require precise control of timing of gene manipulation in cones and RPE; 2) will use innovative conditional overexpress knock-in mouse ; 3)will be the first to test innovative hypothesis that reprogramming cone and RPE metabolism can promote cone survival in RP independently of the underlying rod specific gene mutations; 4) will use unique knock-in mouse model of RP; and 5) will test preclinical animal trial using AAV::Cone specific CRISPR/Cas9 to target a gene to reprogram cellular metabolism.