# Protective function of STAT3-mediated astrocyte reactivity in experimental glaucoma: mechanism of action

> **NIH NIH R01** · SCHEPENS EYE RESEARCH INSTITUTE · 2020 · $47,050

## Abstract

Project Summary
 Glaucoma is a disease in which current treatments focus on modifying a major risk factor, that is
lowering intraocular pressure, rather than directly targeting the pathophysiological mechanisms in the retina or
optic nerve that lead to ganglion cell death. This is because we still do not fully understand the underlying
mechanisms of the disease. In many cases, lowering the intraocular pressure alone is not sufficient, and
patients continue to lose their vision. Identifying new mechanisms that mediate ganglion cell degeneration will
benefit the development of alternative treatments for glaucoma.
 A leading hypothesis in the pathophysiology of glaucoma is that astrocytes within the optic nerve head
play an important role in the ganglion cell degeneration, albeit it is not clear what this role is. Astrocytes are a
key focus because (1) they populate the optic nerve head, a site where early ganglion cell axon injury occurs,
and (2) astrocytes in the optic nerve head become highly “reactive”, a process that changes their morphology,
function and molecular phenotype, but in the white matter of the CNS is not well understood.
 Using a loss-of-function transgenic mouse model, we recently showed that STAT3 signaling is a critical
regulator of astrocyte reactivity within the glaucomatous optic nerve head. Knocking out STAT3 attenuates
astrocyte reactivity, increasing ganglion cell degeneration and visual function loss. Astrocyte reactivity
therefore functions by some mechanism to preserve vision, upturning the long prevailing belief that reactivity is
simply detrimental in disease and that treatments must prevent it.
 Based on this initial observation, the overall goal of our proposed study is to investigate the mechanism
by which astrocyte reactivity affects ganglion cell survival. This study is unique and novel in identifying and
investigating a novel mechanistic pathway (the STAT3 signaling pathway) involved in glaucoma. Our method
is to use targeted deletion of two specific genes from astrocytes to generate a loss-of-function (STAT3
knockout mice) and gain-of-function (SOCS3 knockout mice; the negative feedback molecule of STAT3)
mouse model and determine how these affect histological, functional and molecular outcome measures
following two different models of experiment glaucoma. In a final experiment, we will use a commercially
available pharmacological agent to test the therapeutic potential of manipulating the STAT3 pathway and
astrocyte reactivity towards a beneficial outcome. Our specific aims to accomplish our goal are to test the
following hypotheses: (1) that STAT3 knockout, which attenuates astrocyte reactivity, increases pathological
processes in the glaucomatous optic nerve, particularly processes related to inflammation/immunity, and (2)
that increasing STAT3 activation and enhancing astrocyte reactivity will improve histological and functional
outcome. As glaucoma is the second leading cause of blindness worldwide, this p...

## Key facts

- **NIH application ID:** 10144566
- **Project number:** 3R01EY029268-03S1
- **Recipient organization:** SCHEPENS EYE RESEARCH INSTITUTE
- **Principal Investigator:** Daniel Sun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $47,050
- **Award type:** 3
- **Project period:** 2018-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144566

## Citation

> US National Institutes of Health, RePORTER application 10144566, Protective function of STAT3-mediated astrocyte reactivity in experimental glaucoma: mechanism of action (3R01EY029268-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10144566. Licensed CC0.

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