# Reversal of glutamine/glutamate metabolism and Retinopathy of Prematurity

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2022 · $390,425

## Abstract

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.

## Key facts

- **NIH application ID:** 10491746
- **Project number:** 5R01EY024972-07
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** JONATHAN E SEARS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $390,425
- **Award type:** 5
- **Project period:** 2015-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10491746

## Citation

> US National Institutes of Health, RePORTER application 10491746, Reversal of glutamine/glutamate metabolism and Retinopathy of Prematurity (5R01EY024972-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10491746. Licensed CC0.

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