# Stimulating Retina Regeneration from Muller Cells in Progressive Retinal Degenerations

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $557,186

## Abstract

Inherited retinal degenerations (IRDs) result in the progressive and permanent death of neurons. In
recent years, however, our knowledge of endogenous stem cells in the retina has opened the
possibility of stimulating regeneration of lost neurons in patients suffering from IRDs. Leber's
Congenital Amaurosis (LCA), Bardet-Biedl Syndrome, and Retinitis Pigmentosa are among the most
common form of IRDs. Mutations in CEP290 are one of the most common causes of LCA, while
mutations in BBS2 contribute to BBS and mutations in the EYS gene cause RP. We demonstrate
that zebrafish with mutations in the either cep290, bbs2, or eys genes undergo a progressive cone
degeneration with evidence of rod dysfunction. Unlike mammals, zebrafish have the innate ability to
regenerate retinal neurons when they are damaged or lost. In response to retinal injury, zebrafish
exhibit a robust capability of regenerating lost neurons, including photoreceptors. Retinal damage
causes release of growth factors and inflammatory cytokines that trigger Müller glia to divide and
generate multipotent retinal progenitor cells that regenerate lost neurons. Central to this process is a
reprogramming event that involves activation of Stat3. While robust regeneration occurs following
acute injury, evidence from the literature and preliminary data indicate that regeneration does not
occur in zebrafish with inherited forms of retinal degeneration, such as the cep290-/-, bbs2-/-, or eys-/- mutants. These observations suggest that Müller glia respond differently to acute vs. inherited forms
of retinal injury and that regeneration is only triggered when the degree of retinal injury crosses a
“damage threshold” within a temporal window. In zebrafish degeneration mutants there is
widespread proliferation of rod progenitor cells. However, Müller glia, which are the source of cone
progenitors, fail to proliferate. Using what is known about mechanisms involved in regeneration after
acute retinal injury in zebrafish, we will test components of these signaling pathways to determine if
they are activated in Müller cells of these photoreceptor degeneration mutants. In particular, we will
focus on pathways that converge to activate Stat3. Using RNAseq on purified Muller glia from these
degeneration mutants, we will investigate how degeneration and inflammation alter the transcriptome
of Muller glia. Finally, we will use pharmacological and genetic approaches to suppress immune cell
activity and understand the role of microglia and macrophages on degeneration and regeneration.
Understanding the mechanisms that underpin retinal regeneration in multiple zebrafish disease
models will generate novel hypotheses that can ultimately be translated into humans with retinal
degenerative diseases.

## Key facts

- **NIH application ID:** 9995137
- **Project number:** 1R01EY030574-01A1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Brian D Perkins
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $557,186
- **Award type:** 1
- **Project period:** 2020-05-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9995137

## Citation

> US National Institutes of Health, RePORTER application 9995137, Stimulating Retina Regeneration from Muller Cells in Progressive Retinal Degenerations (1R01EY030574-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9995137. Licensed CC0.

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