# Optineurin dysfunction induces neurodegeneration in normal tension glaucoma by a novel molecular mechanism

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $545,696

## Abstract

PROJECT SUMMARY
Normal tension glaucoma (NTG) is characterized by optic neuropathy with progressive retinal ganglion cell
(RGC) death and optic nerve (ON) degeneration but in the absence of intraocular pressure (IOP) elevation. All
current glaucoma treatments are to lower IOP and are less effective in NTG patients. The primary reasons for
the therapeutic vacuum are the limited understanding of the molecular mechanisms of IOP-independent
glaucomatous degeneration and the lack of a practical and effective NTG animal model. Causal mutations in the
optineurin gene (OPTN) have been found in familial and sporadic NTG. Interestingly, OPTN mutations also
cause inherited forms of another CNS axonopathy, amyotrophic lateral sclerosis (ALS), indicating a common
degenerative machinery that can be activated by dysfunctional OPTN in vulnerable CNS neuronal populations.
However, although OPTN has been extensively studied and its various roles in autophagy, cytokine signaling,
and vesicle trafficking have been found, the pathophysiology role of OPTN in CNS neurodegeneration are far
from clear. We have recently established a highly efficient NTG mouse model by truncating OPTN gene in RGCs
specifically, which presents significant RGCs and ON degeneration within weeks. Using this novel NTG model,
we propose to investigate how OPTN mutation causes neurodegeneration in vivo through validating and
characterizing OPTN-interacting proteins in RGCs and ON. Through these studies, we will generate essential
information to uncover novel molecular mechanisms of glaucomatous neurodegeneration related with OPTN that
may be also shared by ALS and other CNS axonopathies, identify novel modifiers of RGC/ON
neurodegeneration, and provide valuable tools and animal models to develop neuroprotection therapies.

## Key facts

- **NIH application ID:** 10744223
- **Project number:** 5R01EY032518-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Yang Hu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $545,696
- **Award type:** 5
- **Project period:** 2022-02-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10744223

## Citation

> US National Institutes of Health, RePORTER application 10744223, Optineurin dysfunction induces neurodegeneration in normal tension glaucoma by a novel molecular mechanism (5R01EY032518-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10744223. Licensed CC0.

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