# Innate immune system regulation of retinal regeneration

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $446,841

## Abstract

PROJECT SUMMARY
Degenerative vision disorders are caused by the loss of retinal cells. In zebrafish, retinal Müller glial (MG) act
as stem cells, generating MG-derived progenitor cells (MGPCs) which replace lost retinal cells. Mammalian
MG/MGPCs can also produce new retinal neurons, however, proliferative capacity is limited and disease-
relevant cell types (e.g., photoreceptors) are rarely generated. Our goal is to understand why the regenerative
potential of MG/MGPCs are limited in mammals in comparison to a regenerative species (i.e. zebrafish).
In zebrafish, widespread retinal cell loss triggers “developmental” regeneration, producing all major retinal cell
classes. Conversely, selective retinal cell loss results in a “fate-biased” process where MGPCs give rise to the
lost cell type. How MG sense the extent of loss, however, is unknown. As the immune system plays critical
roles during retinal regeneration, we examined the impact of microglia reactivity on MG activation in zebrafish.
We observed that microglia are required for MG stem cell activation and that immunosuppression can inhibit or
enhance regeneration kinetics depending on the treatment timing. We hypothesize that microglia reactivity
levels scale to the extent, duration, and/or specificity of retinal cell loss in order to coordinate MG
activation, MGPC proliferation rates and fat decisions to the type of injury incurred. To test our
hypothesis, here we propose to combine an improved targeted cell ablation system enabling titratable,
sustainable, and selective retinal cell loss with resources/methods for labeling of immune cell types, intravital
timelapse imaging, lineage tracing, and single cell transcriptomics. Specifically we will define how the extent
(Aim 1), the duration (Aim 2) and specificity (Aim 3) of cone photoreceptor or retinal ganglion cell loss impact
immune cell reactivity and retinal regeneration. These experiments will serve to define roles specific immune
cell subtypes play in shaping MGPC proliferation and cell fates during regeneration in zebrafish.

## Key facts

- **NIH application ID:** 10923916
- **Project number:** 5R01EY033009-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** JEFFREY MUMM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $446,841
- **Award type:** 5
- **Project period:** 2022-09-30 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10923916

## Citation

> US National Institutes of Health, RePORTER application 10923916, Innate immune system regulation of retinal regeneration (5R01EY033009-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10923916. Licensed CC0.

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