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Regulation of adult hippocampal function by the neural stem and progenitor cell secretome

Award Number: R01NS124775
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/23/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Regulation of adult hippocampal function by the neural stem and progenitor cell secretome - A unique neurogenic niche in the adult hippocampus hosts neural-lineage stem cells that can persist throughout the lifespan in a wide range of adult mammals. Uncovering the functional role of these stem cells and how they interact with other cell types in the niche can provide insight in to the mechanisms that mediate hippocampal cognitive-emotional functions, as well as potential mechanisms for regenerating tissue in the adult brain. Recently, stem cell secreted proteins (i.e. the stem cell secretome) have emerged as influential players in tissue homeostasis. However, relatively little is known about either the content or the function of the secretome of endogenous neural stem cells and their progenitors (NSPCs) in the adult hippocampus. Our preliminary data reveal that adult hippocampal NSPCs may regulate their microenvironment through the production of the soluble protein, vascular endothelial growth factor (VEGF). We find that NSPCs synthesize large quantities of VEGF in their hippocampal niche and that NSPC-derived VEGF is necessary for sustaining healthy hippocampal function. We propose to investigate the hypothesis that NSPCs support hippocampal function by direct actions of VEGF that suppress neuronal hyperexcitability, ultimately supporting memory function, as well as protecting it from injury. In Aim 1, we will use RNAsequencing as well as genetic code expansion coupled with biorthogonal non- canonical amino acid protein tagging to determine the specific local contributions of NSPCs to VEGF isoforms in the cell layers of the dentate gyrus subregion where these cells reside. In Aim 2, we will use transgenic knockdown and viral rescue models to investigate how dentate gyrus circuit activity is regulated specifically by NSPC-derived VEGF. In Aim 3, we will use transgenic knockdown and viral rescue models to determine how NSPC-VEGF influences hippocampal behavioral functions and vulnerability to excitotoxic injury. The completion of this work will establish a new functional dimension of endogenous NSPCs via their secretome, and advance understanding of how hippocampal health is actively maintained in a unique niche of the adult brain.


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 = $382,277 )
2026	2026	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/30/2026	NON-COMPETING CONTINUATION	$344,049
2026	2026	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	2/28/2026	NON-COMPETING CONTINUATION	$38,228
														Subtotal = $382,277

Issue Date FY: 2025 ( Subtotal = $363,462 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/27/2024	NON-COMPETING CONTINUATION	$344,633
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	1/17/2025	SUPPLEMENT FOR EXPANSION	$18,829
														Subtotal = $363,462

Issue Date FY: 2024 ( Subtotal = $450,062 )
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	3	6/10/2024	NON-COMPETING CONTINUATION	$27,241
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	12/8/2023	SUPPLEMENT FOR EXPANSION	$32,634
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	5/3/2024	SUPPLEMENT FOR EXPANSION	$39,947
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/4/2023	NON-COMPETING CONTINUATION	$350,240
														Subtotal = $450,062

Issue Date FY: 2023 ( Subtotal = $419,529 )
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	2/3/2023	SUPPLEMENT FOR EXPANSION	$30,114
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/2/2022	NON-COMPETING CONTINUATION	$350,474
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/31/2023	NON-COMPETING CONTINUATION	$38,941
														Subtotal = $419,529

Issue Date FY: 2022 ( Subtotal = $389,661 )
2022	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/22/2021	NEW	$389,661
														Subtotal = $389,661

Grand Total All Awards = $2,004,991

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Regulation of adult hippocampal function by the neural stem and progenitor cell secretome

Award Number: R01NS124775

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/23/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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