# Targeting BAX as a Therapeutic for Protection of Retinal Ganglion Cells

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $490,214

## Abstract

BAX is a proapoptotic protein, which is critical for the execution of intrinsic apoptosis in retinal ganglion cells
(RGCs) after optic nerve damage, suggesting that targeting BAX may be an effective therapeutic strategy for
neuroprotection. It has been reported, however, that reducing BAX levels only provides a transient protection to
axons in a mouse model of glaucoma. Whether or not this transient protection is sufficient to allow axons to
recover after elimination of the original stressor, has not been tested.
 Aim 1 will test the protective effect of BAX reduction on the ability of axons to survive and/or recover in
models that mimic the IOP-lowering therapy experienced by patients with ocular hypertension (OHT). Two
models of inducible OHT in mice, microbead injection and steroid induced OHT, will be employed on both wild
type and Bax+/- mice (where reduced BAX more likely mimics a human treatment). In both models IOP levels
can be returned to normal after a desired interval. We will test if reducing BAX protein levels both reduces soma
and axon pathology, and either protects axon function, or allows functional recovery. We will also examine the
effects of controlled experimental IOP (CEI). The advantage of CEI is that it normalizes the IOP insult, which
eliminates the confounding factors of variable IOP associated with other models of OHT.
 Dorsal Root Ganglion cells contain a BAX-dependent degenerative pathway that is activated early and before
other more well-characterized catabolic reactions involving calcium influx. This pathway is activated by a BH3-
only protein produced in the cell soma and then transported to the axon. A similar mechanism in RGC axons
may explain the partial protective effect of BAX reduction. Aim 2 will evaluate the presence of this pathway in
RGC axons where degeneration will be induced in optic nerves ex vivo. We will also interrogate axons for the
presence and localization of key molecules that activate BAX, and molecules that act down-stream of BAX
activation. Preliminary studies suggest that the BH3-only protein NOXA may be an important regulator of BAX
activation in axons. We will explore this in detail using Noxa-deficient mice subjected to induced OHT.
 Protected RGCs silence transcription of genes required for function. New studies show that the committed
process of dying in Bax-deficient cells, is shut down after 8 weeks. Thus cells can be classified into two
categories, those actively dying (AD-mode) and those that have gone quiescent (Q-mode). Aim 3 will investigate
if cells in Q-mode respond differently to 3 attempts to reactivate them, including using HDAC inhibitors to
attenuate the transcriptional silencing of RGC-specific gene expression, the addition of Zymosan and CPT-cAMP
to induce regeneration, or the up-regulation of transcription factors that can specify retinal precursor cells as
RGCs. These experiments will be conducted on RGCs after acute damage to the optic nerve, which serves as
a model ...

## Key facts

- **NIH application ID:** 9918403
- **Project number:** 5R01EY030123-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** ROBERT W NICKELLS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $490,214
- **Award type:** 5
- **Project period:** 2019-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918403

## Citation

> US National Institutes of Health, RePORTER application 9918403, Targeting BAX as a Therapeutic for Protection of Retinal Ganglion Cells (5R01EY030123-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9918403. Licensed CC0.

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