# Modulation of optic nerve head astrocyte reactivity in glaucoma

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $376,673

## Abstract

Project Summary
 The optic nerve head (ONH) is the primary site of axon injury in glaucoma, a neurodegenerative disease
that is the leading cause of irreversible blindness affecting 76 million people worldwide. Elevated intraocular
pressure (IOP) is the only modifiable risk factor for glaucoma, and lowering IOP is the only available strategy to
slow the progression of vision loss. Thus, there is a critical need for novel therapeutic strategies targeting the
site of axon injury within the ONH. In order to develop novel ONH-targeted treatments for glaucoma, we must
determine the early cellular events that lead to ONH axon injury. Astrocytes (local glia within the ONH) provide
structural and metabolic support for axons. In neurodegenerative disorders including glaucoma, astrocytes
become “reactive” and display structural and molecular changes. In several glaucoma models, including ours,
significant ONH astrocyte actin- and intermediate filament-based cytoskeletal reactivity occurs prior to
observable axon injury. Whether IOP-dependent ONH astrocyte reactivity is neuroprotective or helping drive
disease, or whether modulation of these reactive responses alters axon vulnerability to elevated IOP remain
unclear. Using a rodent model of acute IOP elevation, our preliminary data demonstrate that ONH astrocytes
react by retracting their actin-based cellular extensions and reducing connexin43 labeling (an astrocyte gap
junction protein involved in maintaining astrocyte syncytial isopotentiality, and reliant on the actin cytoskeleton
for localization). Furthermore, we show that actin cytoskeletal stabilization (using the Rho kinase inhibitor
fasudil) significantly reduces ONH astrocyte cytoskeletal & gap junction reactivity and protects axons in this
model. Lastly, using an in vivo surgical strategy developed in our lab, we show that ONH astrocytes can be
modulated by local small molecule delivery to the ONH. In this proposal, we will determine the role of ONH
astrocyte cytoskeletal reactivity in axon degeneration after acute IOP elevation, by combining our rodent model
with local and systemic delivery of small molecule modulators of the cytoskeleton. Next, we will examine the
mechanistic role of ONH astrocytic connexin43 in IOP-dependent axon degeneration using small molecule and
genetic strategies to suppress connexin43 in our rodent models. Axon- and astrocyte-specific
immunofluorescence of ONH tissue will be used to determine the extent of axon injury and astrocyte
responses within the ONH at various time points after IOP elevation. In the course of this work, we will address
the role of the ONH astrocyte cytoskeleton and gap junctions in IOP-dependent axon degeneration, as well as
their modulation as a novel strategy for axon protection. The ultimate long-term goal of this project is to bring to
light new astrocyte-specific therapeutic targets to reduce the burden of glaucomatous vision loss worldwide.

## Key facts

- **NIH application ID:** 10456723
- **Project number:** 5R01EY030429-03
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Diana del Carmen Lozano
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $376,673
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10456723

## Citation

> US National Institutes of Health, RePORTER application 10456723, Modulation of optic nerve head astrocyte reactivity in glaucoma (5R01EY030429-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10456723. Licensed CC0.

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