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Microglial plasticity mechanisms in the developing retina

Award Number: R01EY035254
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2027
AWARD TERMINATION DATE: 05/29/2025

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Microglial plasticity mechanisms in the developing retina - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $482,058 )
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Vision Research	000	4	1/28/2026	NON-COMPETING CONTINUATION	$482,058
														Subtotal = $482,058

Issue Date FY: 2025 ( Subtotal = $571,860 )
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Vision Research	002	3	5/29/2025	TERMINATION	$0
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Vision Research	000	3	1/23/2025	NON-COMPETING CONTINUATION	$494,058
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Vision Research	001	3	1/27/2025	SUPPLEMENT FOR EXPANSION	$77,802
														Subtotal = $571,860

Issue Date FY: 2024 ( Subtotal = $535,476 )
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Vision Research	000	2	2/26/2024	NON-COMPETING CONTINUATION	$503,058
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Vision Research	001	2	7/22/2024	SUPPLEMENT FOR EXPANSION	$32,418
														Subtotal = $535,476

Issue Date FY: 2023 ( Subtotal = $526,308 )
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Vision Research	000	1	8/29/2023	NEW	$526,308
														Subtotal = $526,308

Grand Total All Awards = $2,115,702

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Microglial plasticity mechanisms in the developing retina

Award Number: R01EY035254

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2027

AWARD TERMINATION DATE: 05/29/2025

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