# Microglial plasticity mechanisms in the developing retina

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $503,058

## Abstract

PROJECT SUMMARY
Microglia are phagocytic cells that play multiple critical roles in retinal development and ocular diseases. In
parallel, they display remarkable diversity in their functional and molecular states. This suggests that a diverse
portfolio of microglial subtypes is needed in the retina, but the molecules that link microglia state to their function
remain unknown. The objective here is to identify molecular and cellular mechanisms that specify microglia state
changes in the retina. The central hypothesis is that microglia phagocytic states are specified by neurons via a
particular neuron-derived receptor-ligand pair – signal regulatory protein alpha (SIRPα) and CD47. This receptor-
ligand pair constitutes a key “don’t eat me” anti-phagocytic signal in microglia. Preliminary data surprisingly show,
however, that neuron-derived SIRPα is also crucial for regulating microglial phagocytic function and phagocytic
state. Neuronal SIRPα appears to achieve this by acting as a decoy receptor to prevent microglial CD47-SIRPα
signaling, thereby permitting microglia phagocytosis during retinal development. To understand the mechanisms
by which microglia phagocytic states are specified, and to test the neuronal SIRPα-CD47 signaling hypothesis,
three Specific Aims are proposed. First, we will determine when and how neuronal SIRPα alters microglia
diversity and plasticity. These studies will establish whether neuronal SIRPα alters microglia state by
regulating their maturation or by post-developmental changes. Second, we will define how microglia
reconcile conflicting cues that promote different physiological states. These experiments will causally
establish the relationship between ‘eat me’ and ‘don’t eat me’ cues during microglia state selection. Third, we
will Identify developmental events that depend on SIRPα-driven microglial state changes. This aim will
define functional consequences of microglial state changes driven by neuronal SIRPα. In particular, we will test
whether astrocyte death depends on neuronal SIRPα signaling, a hypothesis supported by our preliminary data.
This work will be significant because identification of a neuron-derived mechanism that dictates microglia state
plasticity is unexpected. Thus, completion of this work will change the way we understand how developmental
signals program microglia outcomes. This study will also lay the groundwork for new therapeutic options to
modify retina microglia state and function.

## Key facts

- **NIH application ID:** 10915606
- **Project number:** 5R01EY035254-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Melanie A Samuel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $503,058
- **Award type:** 5
- **Project period:** 2023-09-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10915606

## Citation

> US National Institutes of Health, RePORTER application 10915606, Microglial plasticity mechanisms in the developing retina (5R01EY035254-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10915606. Licensed CC0.

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