Identifying the cause for photoreceptor-mediated retinal-pigmented epithelium atrophy

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PI: Claudio Punzo Project Summary Retinal-pigmented epithelium atrophy (RPE) that results in geographic atrophy (GA) in humans is one of the leading causes for blindness in the industrialized world. This is because there is currently no treatment available to prevent RPE atrophy and thus GA, which is an advanced form of Age-related Macular Degeneration (AMD). The disease is characterized by focal RPE cell loss. Because the RPE maintains photoreceptor homeostasis, photoreceptors die as well, which then leads to blindness. Recently, it has been recognized that the high metabolic demands of photoreceptors may contribute to disease progression in AMD, in particular, because photoreceptors and RPE metabolism are tightly linked. Two key findings imply photoreceptors in disease pathogenesis. First, the distribution of soft drusen and subretinal drusenoid deposits mirrors the distribution of cones and rods, respectively. This has led to the proposal that the metabolic needs of photoreceptors are what drives deposit formation. Second, macular translocation procedures, which were developed to save macular cones from dying RPE cells revealed that the new region where the cones where translocated redeveloped GA. Here it is thought that the high metabolic demands of cones are what causes RPE stress. However, whether photoreceptor metabolism differs between AMD patients and non-diseased individuals remained unclear. We recently showed that PRs of AMD patients display signs of nutrient derivation as they upregulate genes associated with an adaptive response to a glucose shortage. By mimicking this adaptive response in mouse photoreceptors we were able to induce a subset of pathologies that are reminiscent of those seen in humans with AMD, including focal RPE atrophy. The goal of this project is to identify what exactly causes the pathologies seen. We propose in aim 1 to further analyze our model and to determine how RPE cells die. Thereafter, in aim 2, we will dissect genetically the signaling pathway that we have used to manipulate photoreceptor metabolism in order to hone in on the metabolic changes that cause disease. Finally, in aim 3, we will use metabolomics, lipidomics and transcriptomics to identify the underlying gene expression changes that cause disease and test putative candidate mechanisms in vivo. Accomplishment of the proposed research will help understand how photoreceptors can cause RPE atrophy.