# The Mechanism of Sigma 1 Receptor Mediated Neuroprotection in Glaucoma

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2024 · $421,655

## Abstract

The long-term goal of our laboratory is to develop successful neuroprotective treatments for glaucoma.
Glaucoma is a blinding disease for which neuroprotective treatments are desperately needed. In the visual
system, retinal ganglion cells (RGCs) conduct impulses to the visual cortex via RGC axons which form the optic
nerve (ON). Loss of RGCs and their axons are the underlying cellular cause of many optic neuropathies including
glaucoma. RGC axons are particularly vulnerable to damage at the optic nerve head (ONH) where ONH
astrocytes (ONHAs) are the main glial cell. This proposal focuses on sigma-1 receptor (S1R) as a promising
therapeutic target in glaucoma. S1R is a ligand operated molecular chaperone that generally elicits pro-survival
responses via regulation of protein-protein interactions. Although activation of S1R using the canonical ligand
(+)-pentazocine (PTZ) reduces axon loss in a rat microbead model of glaucoma, the cell-specific mechanisms
by which S1R provides this neuroprotection are not well-known. Here, we investigate a novel function of S1R as
a regulator of the ONHA secretome. Previous studies indicate that S1R interacts with proteins mediating
secretion and in vitro experiments suggest that the presence of S1R in ONHAs is required for supporting RGC
health in co-culture experiments. Three specific aims are proposed to investigate the central hypothesis that S1R
mediates neuroprotection in RGCs by regulating the ONHA secretome. Aim 1 uses novel cell-specific S1R
knockout (KO) mice to determine the extent to which S1R in astrocytes versus RGCs is necessary for
neuroprotection using the microbead and silicone oil models of glaucoma. Aim 2 tests the hypothesis that S1R
regulates the ONHA secretome to enable RGC protection. A combination of molecular and genetic approaches
are used to tag, concentrate, and identify secreted proteins in ONHA-conditioned media with/without S1R
activation and in presence/absence of ocular hypertension and ER stress. Comparison of the changing
secretome under different conditions will identify specific components with the potential to promote RGC survival.
Aim 3 addresses the molecular pathways induced in RGCs by the S1R-mediated ONHA secretome. A
combination of in vitro and in vivo approaches will be used to investigate how S1R in ONHAs alters RGC
mitochondrial localization and metabolism. In addition, we will determine transcriptome and translatome changes
that occur in RGCs upon exposure to the ONHA secretome. Successful completion of this proposal will identify
new therapeutic targets within the astrocyte secretome. Modulating the astrocyte secretome offers a novel
druggable approach to mitigate factors leading to RGC death.

## Key facts

- **NIH application ID:** 10882633
- **Project number:** 2R01EY027406-06A1
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Kathryn Bollinger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $421,655
- **Award type:** 2
- **Project period:** 2018-02-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882633

## Citation

> US National Institutes of Health, RePORTER application 10882633, The Mechanism of Sigma 1 Receptor Mediated Neuroprotection in Glaucoma (2R01EY027406-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10882633. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*