Proline metabolism in retinal health

PROJECT SUMMARY/ABSTRACT Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. A common feature in AMD is the early damage of retinal pigment epithelium (RPE), a monolayer of cells between photoreceptors and choroid. RPE controls nutrient transport from choroid blood supply to the outer retina and multiple lines of evidence show that the altered metabolism in RPE is the underlying mechanism for AMD. The long-term goal of this project is to identify key metabolic features of RPE and the roles that they play in AMD. We recently found that besides glucose, RPE preferentially uses proline, an amino acid, to fuel its metabolism. Mutations of enzymes in proline metabolism in humans could cause chorioretinal atrophy or retinal degeneration. The observation that a proline transporter is highly enriched in RPE but not in photoreceptors, further supporting our finding. The proline transporter is a novel risk gene linked to AMD. In our preliminary data, we show that knockout of the proline transporter blocks proine utilization and impairs visual function. The objective of this proposal is to study proline metabolism in RPE and its role in retinal degeneration. We plan to rigorously investigate the role of proline in healthy and diseased RPE using advanced tracer methodology, mass spectrometry, in vivo infusion, live imaging, and proline transporter knockout mouse models. The outcome of this research will be to establish a conceptual framework for RPE metabolism that describes how RPE uses nutrients to maintain metabolic homeostasis with the outer retina. This new knowledge will provide the basis for understanding the mechanisms of AMD and lay the foundation for developing new treatments.