# Metabolic Vulnerability as a Diseased Target for Glaucoma

> **NIH NIH R01** · UNIVERSITY OF NORTH TEXAS HLTH SCI CTR · 2024 · $9,081

## Abstract

Project Summary
 Retinal ganglion cell (RGC) axons degenerate after functional decline in glaucoma, a
circumstance potentially caused, but certainly exacerbated by, energy deficit, indicating
that metabolic dysfunction contributes to glaucomatous degeneration. High intraocular
pressure (IOP) in glaucoma results in hypoxia that promotes glycolysis through
upregulation of glycolysis-associated genes, but also mitochondrial recycling, and
downregulation of genes encoding for oxidative phosphorylation (OxPhos). A critical
question is whether RGC metabolic reprogramming from OxPhos to glycolysis is
initiated by IOP-associated hypoxia, and whether repeated reprogramming and
development of pseudohypoxia underlies the energy stress and dysfunction observed in
the glaucomatous retina.
 The long-term goal of this work is to leverage our understanding of retinal metabolism
to maintain visual function despite the stressors inherent in glaucomatous
neurodegeneration. The overall objective of this proposal is to determine the impact of
IOP-mediated damage on retinal and optic nerve head metabolic resilience. Our central
hypothesis is that ocular hypertension (OHT)-associated hypoxia transitions into
pseudohypoxia, destabilizing neural and glial metabolism and mitochondrial
homeostasis, with downstream negative impact on RGCs in the retina and ONH. This
hypothesis derives from our recent analysis indicating that mitochondria and availability
of energy substrates, both targets of hypoxia-associated regulation, contribute to the
metabolic challenges of RGCs. The rationale for the work is that investigating metabolic
cooperation and dysfunction in glaucomatous retina will identify new therapeutic targets
for a disease that has no mechanism-based interventions.
 Guided by strong preliminary data, the aims of this proposal will address a critical
element of the retinal energy management in glaucoma by revealing 1) whether OHT is
the impetus for metabolic reprogramming, followed by adaptation as pseudohypoxia, in
the glaucomatous retina; 2) how metabolic coupling is managed among neurons and
glia in the normal and ocular hypertensive retina; 3) how RGCs, Müller glia, and ONH
astrocytes respond to and manage metabolic challenge on a cell-by-cell basis. Overall,
this work will enable us to determine how RGCs, Müller glia, and ONH astrocytes
respond metabolically to IOP increase, whether those changes persist long-term, and
how we might promote metabolic resilience. The approach is innovative by taking the
position that insight will only come from investigating the metabolic dependencies of the
primary cell types impacted during the development of glaucoma pathology. In addition,
we will apply new cutting-edge approaches to the investigation of mitochondria such as
cell-specific mitochondrial isolation followed by metabolomics and co-detection of
protein and gene expression through spatial transcriptomics. This proposal is significant
because we will reveal mitochondria...

## Key facts

- **NIH application ID:** 11042310
- **Project number:** 3R01EY026662-08S1
- **Recipient organization:** UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
- **Principal Investigator:** DENISE M INMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $9,081
- **Award type:** 3
- **Project period:** 2016-04-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11042310

## Citation

> US National Institutes of Health, RePORTER application 11042310, Metabolic Vulnerability as a Diseased Target for Glaucoma (3R01EY026662-08S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11042310. Licensed CC0.

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