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Novel Modulators of TGFß1 signaling in regulation of remyelination by neural stem cells

Award Number: R01NS119517
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: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Novel Modulators of TGFß1 signaling in regulation of remyelination by neural stem cells - ABSTRACT Loss of oligodendrocytes gives rise to demyelination, ultimately resulting in axonal degeneration and debilitating clinical outcomes in diseases like Multiple Sclerosis. While remyelination can prevent neurodegeneration, there are currently no approved therapies for promoting remyelination. Thus, there is an urgent need to identify factors that control remyelination. Neural stem cells in the adult subventricular zone are one of the sources of remyelinating oligodendrocytes. These cells are a heterogeneous population that show diverse responses to signaling pathways in the healthy vs demyelinated brain. We have studied one such pool marked by Gli1, which generates remyelinating oligodendrocytes only in response to demyelination. Our previous work showed that the recruitment and differentiation into oligodendrocytes leading to functional recovery is increased substantially by loss of Gli1 in this pool of neural stem cells; however the molecular mechanisms involved in this repair is not known. Through a transcriptomic analysis comparing gene expression in neural stem cells with and without Gli1 expression, we identified the TGFβ1 pathway as a major regulator of remyelination mediated by neural stem cells. However, the effects of TGFβ1 signaling are context dependent and differ with the cell-type, timing and dosage suggesting the presence of specific modulators of the pathway in different cells. Using a combination of bioinformatic analysis and remyelination studies in mice, we discovered a novel mediator of the TGFβ1 pathway, Gpnmb which is highly expressed along with its receptor CD44 in neural stem cells in response to demyelination. In the first aim, we will define the cell-autonomous function of Gpnmb in neural stem cells and its role in remyelination by neural stem cells. In the second aim, we will determine the impact of paracrine Gpnmb signaling through CD44 receptor on remyelination mediated by neural stem cells. In the third aim, we will elucidate the mechanisms of regulation of Gpnmb by TGFβ1 ligand and reciprocal modulation of the TGFβ1 pathway by Gpnmb. For the remyelination studies, we will use the toxin induced models of demyelination. To define the molecular mechanisms of the TGFβ1-Gpnmb signaling pathway, we will utilize in vitro neural stem cell cultures from adult mouse brain. Together, these studies will help identify therapeutic targets for promoting remyelination.


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: 2025 ( Subtotal = $335,675 )
2025	2025	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/25/2024	NON-COMPETING CONTINUATION	$335,675
														Subtotal = $335,675

Issue Date FY: 2024 ( Subtotal = $357,048 )
2024	2024	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	3	5/15/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$88,902
2024	2024	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	5/14/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$25,766
2024	2024	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/21/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$331,282
2024	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	2	5/15/2024	NON-COMPETING CONTINUATION	-$88,902
2024	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/20/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $357,048

Issue Date FY: 2023 ( Subtotal = $382,090 )
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	2/1/2023	NON-COMPETING CONTINUATION	$38,209
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/3/2023	NON-COMPETING CONTINUATION	$343,881
														Subtotal = $382,090

Issue Date FY: 2022 ( Subtotal = $382,090 )
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/24/2021	NEW	$382,090
														Subtotal = $382,090

Grand Total All Awards = $1,456,903

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Novel Modulators of TGFß1 signaling in regulation of remyelination by neural stem cells

Award Number: R01NS119517

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: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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