# Neuroprotection by Modulating ER Stress in Glaucoma

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $416,615

## Abstract

PROJECT SUMMARY
Glaucoma is the most common cause of irreversible blindness and will affect more than 100 million people
between 40 to 80 years old by 2040. It causes severe visual loss due to degeneration of optic nerve (ON) and
retinal ganglion cells (RGCs). There is a significant unmet clinical need for neuroprotectants. Our previous
studies of ON traumatic injury and glaucoma demonstrated that both acute and chronic ON injury induce
endoplasmic reticulum (ER) stress in RGCs. We were able to protect the injured RGC soma and axons if we
blocked the detrimental effects of ER stress by manipulating two key downstream molecules of the unfolded
protein response (UPR) in opposite ways: a) deletion of CCAAT/enhancer binding protein homologous protein
(CHOP), and/or b) activation of X-box binding protein 1 (XBP-1). Thus axon injury-induced ER stress may be a
common mechanism of neuronal damage and targeting neuronal ER stress may have considerable therapeutic
neuroprotective potential in diseases associated with axonopathy. As the first step, we propose to identify
novel ER stress modulators by screening chemical libraries with cell-based high throughput screen (HTS)
assays; and then to validate whether these agents promote RGC and ON survival and preserve visual function
in mouse glaucoma models. Recently, exciting recent studies of axonal Wallerian degeneration have shown
that several key molecules involved in axonal NAD+ metabolism are critical for axonal degeneration. SARM1
(Sterile Alpha and TIR Motif 1), for example, is negatively regulated by axonal NAD+ synthetic enzyme
nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) to induce axon degeneration; deletion of
SARM1 or activation of axonal NMNATs results in axon protection. Thus, we will test the hypothesis that
modulating both intrinsic neuronal ER stress and NAD+ metabolism will synergistically prevent both
RGC soma and axon (ON) degeneration and preserve vision in glaucoma. This study may generate novel
combinatory therapeutic strategies that lead to more efficient neuroprotection in patients. And finally, we will
develop novel in vivo imaging tools for RGC morphology and function studies and acquire much needed
insights into the mechanism of RGC ER stress initiation. We expect the results through these studies will
provide essential information for clinical application of ER stress modulation, and establish translatable
techniques and biomarkers that will greatly facilitate clinical management of glaucoma patients.

## Key facts

- **NIH application ID:** 10114286
- **Project number:** 5R01EY023295-08
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Yang Hu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $416,615
- **Award type:** 5
- **Project period:** 2013-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10114286

## Citation

> US National Institutes of Health, RePORTER application 10114286, Neuroprotection by Modulating ER Stress in Glaucoma (5R01EY023295-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10114286. Licensed CC0.

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