The goal of this proposal is to develop a safe method of protecting retinal blood vessels from oxygen induced retinopathy associated with premature birth. Oxygen therapy is necessary to prevent mortality in these infants but is harmful to premature retinal tissue. Oxygen induced retinopathy, known as retinopathy of prematurity (ROP), blinds 150,000-200,000 children worldwide annually. Quantitative analysis of retinal and lung vasculature in mouse and rat models of human ROP demonstrate that preservation of hypoxia inducible factor (HIF) activity through HIF prolylhydroxylase domain protein (PHD) inhibition safely prevents oxygen-induced lung disease and retinopathy (OIR). We have definitively demonstrated that our systemic strategy of PHD inhibition creates synergy between the liver and the eye through liver specific HIF-1α activation. Our studies using untargeted metabolic profiling of liver, retina, and serum from HIF-1 stabilized wild type mice revealed the completely novel finding that hepatic ureagenesis and retinal ammonia assimilation is HIF-1 dependent. Our isotopic based metabolic experiments using hyperoxic retina support the importance of ammonia assimilation to protection because they reveal an oxygen-induced derangement in glutamate/glutamine cycling in Müller cells that increases the need to assimilate ammonia released by this process. These findings make HIF stabilization a unified approach to preventing ROP by biochemically addressing both hyperoxia of prematurity (by stabilizing HIF in hyperoxia) and separation from the maternal circulation (by stimulating the liver to upregulate protective metabolic pathways) in order to protect lung, and CNS tissues such as the retina and brain. The specific goal of this application is to discover how metabolic change induced by hyperoxia, described as glutamine-fueled anaplerosis, is compensated by HIF-1 dependent metabolic plasticity and ammonia assimilation.