# Regulation of RPE degeneration by REV-ERBalpha

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $533,218

## Abstract

Project Summary
Degeneration of retinal pigment epithelium (RPE) causes vision loss in age-related macular degeneration
(AMD) and retinitis pigmentosa (RP). Promoting survival of RPE (and thereby photoreceptors) is critical for
preserving vision. Whereas many factors contribute to RPE degeneration in eye diseases including both
genetic and environmental ones, oxidative stress is one of the major contributors to RPE dysfunction and
degeneration, derived primarily from excess mitochondrial oxidative products, and phagocytosis-related lipid
oxidation. However, the processes through which dysregulated oxidative stress leads to RPE dysfunction and
degeneration in eye diseases remain incompletely defined. Moreover, there is lack of effective approaches to
promote RPE health and survival. Identification of the basic molecular links which sense RPE redox
(reduction/oxidation) environment to impact RPE dysfunction and degeneration will aid in the identification of
new molecular targets to rejuvenate endogenous cellular defense system in aging RPE and prevent vision loss
in eye diseases. In this project we identified a redox-sensing nuclear receptor REV-ERBα, which may act as a
transcriptional regulator linking RPE redox homeostasis and RPE antioxidant defense to impact RPE
degeneration. REV-ERBα, functioning as a redox- and ligand-dependent transcription factor, controls multiple
biological processes including cellular metabolism, inflammation, and circadian rhythm. Our preliminary results
show that: 1) REV-ERBα levels decline with aging in RPE; 2) genetic deletion of REV-ERBα in mice leads to
age-related development of RPE degeneration, with subretinal deposits, impaired visual function and
dampened RPE phagocytic function; 3) RPE specific deletion of REV-ERBα causes similar fundus lesions; 4)
REV-ERBα deficiency exacerbates chemically-induced induced RPE damage and retinal toxicity in vivo and in
vitro; 4) activation of REV-ERBα protects RPE in vitro and in vivo; and 5) REV-ERBα directly regulates nuclear
factor erythroid-2 related factor 2 (NRF2) transcription and its associated antioxidant genes. We hypothesize
that REV-ERBα is a novel redox-sensitive regulator of RPE intracellular antioxidant defense system, and
activating REV-ERBα is a new way to protect RPE. This hypothesis will be evaluated with both genetic and
pharmacological approaches of modulating REV-ERBα in both acute and chronic models of RPE damage and
degeneration. Mechanistically this work will explore whether REV-ERBα protects RPE vial enhancing RPE
antioxidant self-defense. This proposed work will uncover novel molecular regulatory mechanisms underlying
RPE degeneration, and new druggable molecular targets for developing improved strategies to counter RPE
damage and degeneration in eye diseases.

## Key facts

- **NIH application ID:** 10029720
- **Project number:** 1R01EY031765-01
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** JING CHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $533,218
- **Award type:** 1
- **Project period:** 2020-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10029720

## Citation

> US National Institutes of Health, RePORTER application 10029720, Regulation of RPE degeneration by REV-ERBalpha (1R01EY031765-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10029720. Licensed CC0.

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