# Cell Death Pathways in Glaucomatous Neurodegeneration

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2021 · $553,716

## Abstract

Vision loss in glaucoma is caused by the death of the output neurons of the retina, the retinal ganglion cells.
While it is unclear how retinal ganglion cells are injured in glaucoma, there are considerable data supporting
axonal injury as an early, critical insult in glaucoma. In fact, it is thought that retinal ganglion cell axons are injured
as they exit the eye through a specialized structure called the lamina cribrosa. Despite knowing the likely location
of the glaucomatous insult, the earliest pathological responses to ocular hypertension within retinal ganglion cells
are undefined. It is perhaps not surprising that these events have been difficult to define because the pathological
responses are likely activated only transiently, in a small region of the axon (as they travel through the lamina),
and only in a subset of axons at any given time. We and others have shown that after an axonal insult, distinct
molecular pathways control degeneration of different retinal ganglion cell compartments. However, we do not
know how a very local axonal injury response irreversibly activates somal and axonal degenerative programs.
Here, we describe experiments that will define the molecular pathways controlling and linking the
compartmentalized response of retinal ganglion cells to an ocular hypertensive insult. Our central hypothesis is
that ocular hypertension activates axonal injury signaling pathways that regulate compartment-specific
degeneration processes, and inhibiting these processes will prevent glaucomatous neurodegeneration. To test
this hypothesis, we will perturb these pathways in ocular hypertensive models of glaucoma and assess the
effects on somal and axonal degeneration. Furthermore, we will examine how inhibiting these pathways alters
key aspects of retinal ganglion cell injury response, including axonal transport and retinal ganglion cell function.
Also, we will define the transcriptomic changes within retinal ganglion cells that contribute to ocular hypertension-
induced retinal ganglion cell death. Overall these experiments will provide an integrated understanding of the
pathological signaling that controls glaucomatous neurodegeneration. Given the importance of axonal insult and
axonal degeneration in glaucoma, these experiments will likely identify novel targets for developing
neuroprotective treatments for glaucoma.

## Key facts

- **NIH application ID:** 10232389
- **Project number:** 5R01EY018606-12
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** SIMON W JOHN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $553,716
- **Award type:** 5
- **Project period:** 2008-01-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10232389

## Citation

> US National Institutes of Health, RePORTER application 10232389, Cell Death Pathways in Glaucomatous Neurodegeneration (5R01EY018606-12). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10232389. Licensed CC0.

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