The broad, long-term objective of this proposal is to develop a safe method of protecting blood vessels from oxygen induced toxicity. Oxygen therapy for premature infants is paradoxical: oxygen is necessary to prevent mortality in these children but is toxic to premature retinal tissue. Oxygen toxicity to the premature retina, known as retinopathy of prematurity (ROP), blinds 75-100,000 children world wide annually. Quantitative analysis of retinal vasculature in mice and rats using both sustained and fluctuating oxygen protocols that are models of human ROP demonstrate that preservation of hypoxia inducible factor (HIF) activity through HIF prolylhydroxylase domain protein (PHD) inhibition (HIF PHi) safely prevents oxygen-induced retinopathy (OIR) in mice and rats. We have definitively demonstrated that our systemic strategy of prolyl hydroxylase inhibition requires live specific HIF-1 activation to protect retinal capillary beds. These findings make liver specific HIF PHi 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 secrete protective factors). The specific goal of this application is to determine the molecular mechanism of how hepatic HIF-1 stabilization protects retinal blood vessels.
High blood oxygen concentrations are required to keep premature infants alive but obliterate developing blood vessels in the premature retina. Absent perfusion of the retina drives pathologic angiogenesis to cause the most common form of childhood blindness known as retinopathy of prematurity (ROP). Current vision sparing strategies are implemented after retinal ischemia develops and therefore do not alter the pathogenic basis of ROP. By contrast, hypoxia mimesis, or stabilization of hypoxia inducible factor (HIF), can promote blood vessel protection. We view hypoxia mimesis as an acceptable non invasive approach for the treatment of ROP. This project will investigate the mechanism of hypoxia mimesis to develop this strategy as a therapy to prevent ROP.
| Hoppe, George; Yoon, Suzy; Gopalan, Banu et al. (2016) Comparative systems pharmacology of HIF stabilization in the prevention of retinopathy of prematurity. Proc Natl Acad Sci U S A 113:E2516-25 |
