Wednesday, February 5, 2025 2/5/2025

TGF-b superfamily signaling in controlling Th17 cell function in autoimmune neuroinflammation

Award Number: R01AI160774
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary: Multiple sclerosis (MS) is a debilitating autoimmune neuroinflammation disease inflicting millions of people worldwide. It is caused by dysregulated adaptive and innate immunity. CD4 T cells critically contribute to MS development in humans and EAE development in mice. Particularly, Th17 cells are central to autoimmune neuroinflammation. To understand the etiology of and develop treatment for MS, one of the main goals of MS research is to understand how T cell and Th17 cell function are controlled. Transforming growth factor–β (TGF-β) is instrumental in Th17 cell differentiation and function. Yet it is unclear whether and how TGF-β superfamily member other than TGF-β controls Th17 cell differentiation in MS/EAE. Our recent findings revealed novel TGF-β superfamily and related signaling to regulate Th17 cell function and the development of autoimmune neuroinflammation: (1) SKI protein, a TGF-β signaling suppressor that is degraded upon TGF-β stimulation, suppresses Th17 cell differentiation in vitro and in vivo, (2) SKI expression in T cells completely protected mice from EAE, (3) Activin-A, a TGF-β superfamily member that is closely related to TGF-β, was upregulated during EAE and in activated T cells in inflamed tissues and in the presence of proinflammatory cytokines, and (4) Activin-A+IL6 induced SKI degradation and the differentiation of Th17 cells that phenotypically resemble pathogenic- rather than non-pathogenic-Th17 cells to promote EAE. We therefore hypothesize that TGF-β superfamily member Activin-A is a novel factor distinct from TGF-β to promote pathogenic Th17 function and autoimmune neuroinflammation through SKI. In this study, we proposed to reach the following three Aims. AIM 1: Address whether Activin-A is required for Th17 cell function and EAE. AIM 2: Reveal the molecular program of Activin-A induced Th17 cell generation and function; AIM 3: Investigate the mechanisms underlying SKI controlled Th17 cell function and EAE. There is a great and yet unmet need in the understanding of how Th17 cell function during autoimmune neuroinflammation. This study aims to reveal previous unappreciated cellular and molecular mechanisms underlying TGF-β superfamily signaling in controlling Th17 cell differentiation and function for autoimmunity. The success of this study will gain critical mechanistic insights into T cell mediated autoimmune neuroinflammation and shed new light on how to mitigate related disease by targeting TGF-β superfamily signaling pathways.


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 = $371,180 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	5	12/6/2024	NON-COMPETING CONTINUATION	$371,180
														Subtotal = $371,180

Issue Date FY: 2024 ( Subtotal = $382,837 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	4	12/21/2023	NON-COMPETING CONTINUATION	$344,553
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	001	4	5/20/2024	NON-COMPETING CONTINUATION	$38,284
														Subtotal = $382,837

Issue Date FY: 2023 ( Subtotal = $383,009 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	3	12/14/2022	NON-COMPETING CONTINUATION	$383,009
														Subtotal = $383,009

Issue Date FY: 2022 ( Subtotal = $383,176 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	2	12/10/2021	NON-COMPETING CONTINUATION	$383,176
														Subtotal = $383,176

Issue Date FY: 2021 ( Subtotal = $383,339 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	001	1	1/22/2021	NEW	$0
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	1	1/15/2021	NEW	$383,339
														Subtotal = $383,339

Grand Total All Awards = $1,903,541

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TGF-b superfamily signaling in controlling Th17 cell function in autoimmune neuroinflammation

Award Number: R01AI160774

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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