# Homeostatic Role and Therapeutic Potential of the Neuroprotective Retinal Lipoxin Circuit

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $489,999

## Abstract

Project Summary/Abstract
Glaucoma is a chronic degeneration of the retina and optic nerve, and a leading cause of irreversible
blindness, estimated to afflict 80 million people worldwide. It is also the most common neurodegenerative
disease in the world, affecting ~3 million Americans with an estimated $2.9 billion annual burden to the US
Health Care system. Our understanding of the etiology and molecular mechanisms that drive the pathogenesis
of glaucoma remain incomplete. Primary treatment options are limited to lowering intraocular pressure (IOP).
There are no neuroprotective therapies to prevent or rescue the degenerative cascades that define glaucoma.
Astrocytes are a central driver of structural and parainflammatory changes at the optic nerve head (ONH) and
subsequent, irreversible retinal ganglion cells (RGC) death. Emerging evidence indicates that astrocytes have
neuroprotective and pro-survival activities in glaucoma. The nature and relevance of these protective signals
remains unclear. We recently identified a secreted neuroprotective activity in resting retinal astrocytes, which
proved to be a previously unknown resident retinal lipoxin lipid mediator circuit. Lipoxins are a family of potent
specialized proresolving lipid mediators (SPMs), which are being developed as drug targets due to their
established role in dampening and resolving local inflammation in other tissues. We discovered that two
lipoxins, LXA4 and LXB4, are generated by resting astrocytes and in the healthy retina and OHN and that a
lipoxin receptor is selectively expressed in RGCs, which identified a previously unknown direct neural activity
of lipoxins. This intrinsic pathway is dysregulated in response to retinal/ONH stress. More importantly, we
established that therapeutic treatment with lipoxins is neuroprotective by increasing RGC survival and rescuing
RGC function in both an acute neurotoxic retinal injury model, and a chronic IOP dependent model of
glaucoma like neurodegeneration. We hypothesize that the lipoxin circuit is an important paracrine signaling
mechanism to maintain neuronal homeostasis and protect the retina against stress. In a multiple-PI Research
Project, we will characterize this novel neuroprotective network, define its mechanism of action and explore the
efficacy of amplifying the lipoxin circuit as a therapeutic target for neuroprotection with the following three
specific aims: 1) Characterize the mechanism of LXA4 and LXB4 formation in retina, ON, and astrocytes in the
context of health and glaucomatous injury, 2) Define the distinct mechanisms of action for LXA4 and LXB4 pro-
survival signaling in RGCs, and 3) Investigate the therapeutic potential of amplifying lipoxin circuits to prevent
and/or stop RGC degeneration. This goal of this project is to generate transformative insights into a novel
neuronal support mechanism and its dysregulation following injury or stress. Most importantly, we will test if
amplification of this protective circ...

## Key facts

- **NIH application ID:** 9896604
- **Project number:** 1R01EY030218-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** JOHN G FLANAGAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $489,999
- **Award type:** 1
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896604

## Citation

> US National Institutes of Health, RePORTER application 9896604, Homeostatic Role and Therapeutic Potential of the Neuroprotective Retinal Lipoxin Circuit (1R01EY030218-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9896604. Licensed CC0.

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