# Understanding metabolic mechanisms underlying retinopathy of prematurity

> **NIH NIH R21** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $195,455

## Abstract

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.

## Key facts

- **NIH application ID:** 10475306
- **Project number:** 5R21EY033046-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Charandeep Singh
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $195,455
- **Award type:** 5
- **Project period:** 2021-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10475306

## Citation

> US National Institutes of Health, RePORTER application 10475306, Understanding metabolic mechanisms underlying retinopathy of prematurity (5R21EY033046-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10475306. Licensed CC0.

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