# Targeting Sigma 1 receptor as a novel therapy for limiting neurovascular injury in ROP

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2024 · $385,000

## Abstract

PROJECT SUMMARY
Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. A pivotal aspect of early ROP
is an arrest in physiologic retinal vascular development. The retinal avascularity and consequent hypoxia
leads to proliferative blinding neovascularization (NV). Ischemia induces retinal cell dysfunction and
irreversible cell damage. NV aggravates vision deterioration. However, current clinical standard-of-care
targeting abnormal retinal NV does not improve and may even impair vision. The driving concept in this
proposal is to create a favorable retinal environment for cell survival, vascular repair and revascularization
of ischemic retina. Multiple retinal cell types participate in shaping retinal environment, including vascular
endothelial cells (ECs), retinal myeloid elements/microglia/macrophages (RMCs), and neuronal elements
such as retinal photoreceptor cells (PRCs) and retinal ganglion cells (RGCs). The underlying mechanisms
for these cellular and molecular activities remain poorly defined. Sigma 1 Receptor (Sig1R), a unique
molecular chaperone, offers a novel approach to favorably enhance the retinal environment under disease
states. Activation of Sig1R provides protection against two major facets of the ischemic retina: oxidative
stress and inflammation. The PI’s previous research indicated powerful retinal neuroprotection of Sig1R in
retinal neurodegenerative diseases. Sig1R activation showed profound neuroprotection in retinal neurons
including PRCs and RGCs. Most-recent independent research by the PI has explored the role of Sig1R in
retinal vascular diseases including ROP. The PI’s preliminary data showed that: i) activation of Sig1R by its
ligand (+)-pentazocine ((+)-PTZ) can markedly protect against avascularity and NV in oxygen-induced
retinopathy (OIR, model of ROP); ii) (+)-PTZ administration significantly rescues impaired visual function in
OIR mice; iii) (+)-PTZ treatment inhibits the release of proinflammatory and proangiogenic factors in OIR
retina; iv) Sig1R knockout delays retinal vascular development at postnatal day 3. The next steps to assess
this promising bi-functional (vascular and neuronal) therapeutic potential will be to characterize the novel
role of Sig1R in retinal normal vascular development and vascular damage in OIR model, and further to
identify which cell types/molecules are modulated/targeted by Sig1R in its reprogramming of the retinal
response to ischemia in OIR. I propose to test the hypothesis that Sig1R acts as a novel key modulator of
normal retinal vascular development and neurovascular damage in OIR, limits vascular injury by promoting
reparative microglia/macrophages via inhibition of proinflammatory and proangiogenic factors, and provides
a novel neurovascular therapy for ROP. We propose three specific aims. 1) Characterize the role of Sig1R
in normal retinal vascular development and vascular damage in OIR model. 2) Test the hypothesis that
Sig1R limits vascular injury by pr...

## Key facts

- **NIH application ID:** 10914256
- **Project number:** 5R01EY035411-02
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Jing Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914256

## Citation

> US National Institutes of Health, RePORTER application 10914256, Targeting Sigma 1 receptor as a novel therapy for limiting neurovascular injury in ROP (5R01EY035411-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10914256. Licensed CC0.

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