# Cellular and Molecular Dynamics of Retinal Microglial in the Context of Photoreceptor Degeneration

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $605,942

## Abstract

ABSTRACT
While outer retinal degenerative diseases, including age-related macular degeneration (AMD) and certain
inherited retinal degenerative diseases, continue to experience technological advances towards better clinical
management, there is still a massive unmet medical need for millions of these patients worldwide.
Pathophysiologically, dead and dying photoreceptors and their toxic byproducts can impede retinal pigment
epithelial (RPE) phagocytosis of photoreceptor outer segments, negatively affect the recycling of visual
pigments, contribute to changes in the metabolite flux patterns, and promote secondary death of
photoreceptors and RPE. Our lab demonstrated direct evidence that microglia are central to the swift
elimination of dead and dying photoreceptor debris; and, in so doing, these microglia mitigate secondary
damage of photoreceptors and RPE associated with degeneration. Our single cell RNA-seq analysis of
microglia from acute, inherited, and age-related photoreceptor degeneration models, guided our additional
series of experiments enabling us to demonstrate that these protective microglia mediate their responses from
the subretinal space. Taking advantage of human postmortem AMD eyes, we found parallels of these microglia
at the transcriptome level, with protein markers, and tissue distribution, potentially suggesting the existence of
a conserved protective response. Still, the specific elements of the photoreceptor debris which are eliminated
by these microglia to protect the outer retina from secondary damage is not known. Also, given that
phagocytosis is energetically demanding, how these microglia obtain the requisite fuel in a lactate rich
environment to fulfill their role is not understood. Lastly, as microglia are highly plastic cells whose functions
are influenced by the microenvironment, the retinal factors that instruct these protective microglia is also not
fully known. To address these fundamental gaps in knowledge we will perform lipidomics to elucidate the toxic
compounds eliminated by protective microglia. Separately, we will leverage genetic knockout mice established
for perturbation of metabolic transporters to elucidate how these microglia are fueled. Lastly, we will perform
RNA-seq to uncover how the cells of the retina shape the function of these protective microglia. With the
expertise of key collaborators to help execute and interpret data generated by these incisive experiments, our
project is successfully positioned to provide a new understanding of retinal resilience mechanisms in the
modulation of microglia that modify the progression of outer retinal degeneration, ultimately providing new
opportunities for the development of novel treatment strategies in preserving vision in patients with retinal
degenerative diseases.

## Key facts

- **NIH application ID:** 10976702
- **Project number:** 2R01EY030906-05
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Daniel Raphael Saban
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $605,942
- **Award type:** 2
- **Project period:** 2020-08-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10976702

## Citation

> US National Institutes of Health, RePORTER application 10976702, Cellular and Molecular Dynamics of Retinal Microglial in the Context of Photoreceptor Degeneration (2R01EY030906-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10976702. Licensed CC0.

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