Understanding metabolic mechanisms underlying retinopathy of prematurity

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Premature infants are born with underdeveloped lungs, making it necessary to provide them oxygen supplementation to prevent mortality. However, the supplemental oxygen provided is deleterious to the developing retina and leads to retinopathy of prematurity. In utero, retinal blood vessels sprout and migrate from high oxygen to low oxygen concentrations by sensing hypoxia. Like in human ROP, hyperoxia leads to blood vessel growth arrest in phase 1 in the mouse model of OIR, which subsequently leads to local hypoxia in the retina and causes neovascularization in phase 2 of OIR. Hypoxia stabilizes hypoxia inducible factor (HIF) which leads to the secretion of angiogenic growth factors like VEGF. Gradient of these growth factors drive tip cell migration and stalk cell proliferation. There is a growing body of evidence suggesting that growth factors are guiding cues; however, biosynthetic metabolites are also necessary for normal development of blood vessels. Recent findings from lab and other groups demonstrate that glutamine is an important metabolite needed for retinal endothelial cell proliferation. In addition to glutamine, endothelial cells also have enhanced glycolytic, pentose phosphate pathway and fatty acid utilization fluxes during proliferation. Glutamine is solely produced by the Müller cells in the retina. Müller cells in normal conditions produce glutamine by assimilating ammonium waste. We have recently demonstrated that hyperoxia decreases glycolytic flux entry into tricarboxylic acid cycle (TCA) in the retinal Müller cells, consequently leading to increased utilization of glutamine by Müller cells and starving retinal endothelial cells of their growth precursor. Preventing blood vessel growth arrest in the phase 1 of OIR may provide protection against phase 2 of OIR. We will use OIR resistant and OIR susceptible mice strains to evaluate biosynthetic metabolic pathways in the phase 1 of OIR. Published data and our preliminary data points towards higher fatty acid metabolism flux in the OIR resistant mouse strains. We hypothesize that the higher triglyceride levels may mitigate or diminish blood vessel proliferation defect completely, by producing acetyl- CoA or succinyl-CoA via fatty acid oxidation when glycolytic carbon entry into TCA is decreased. This can additionally lower glutamine utilization by the Müller cells thereby sparing glutamine for other cell types in the retina. Additionally, supplementing diets of the susceptible mouse with alternative fatty acids as non-nitrogenous anaplerotic substrates may protect susceptible strain against OIR. Understanding these basic metabolic differences between an OIR resistant and an OIR susceptible strain will shed light on the metabolic pathways underlying protection in the OIR resistant mouse strain and may lead to translatable treatment.