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Molecular regulation of TLR2-mediated autoimmune inflammation

Award Number: R01AI141596
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/15/2018
PERIOD OF PERFORMANCE END DATE: 10/31/2025

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Molecular regulation of TLR2-mediated autoimmune inflammation - SUMMARY The mechanisms governing CD4+ T cell activation and function in autoimmune disease remain insufficiently understood even though autoreactive CD4+ T cells are central orchestrators for the initiation and progression of virtually all autoimmune diseases. Multiple sclerosis (MS), a demyelinating disease of the central nervous system (CNS), is a well characterized example of how the failure to control autoreactive CD4+ T cells can lead to devastating inflammation and tissue damage. Encephalitogenic CD4+ T helper (Th) cells, especially Th17 and Th1 cells, promote CNS inflammation by responding to self-antigens both in MS and the murine MS model, experimental autoimmune encephalomyelitis (EAE). Our seminal work has identified an innate-like receptor with critical roles in driving the pathogenicity of encephalitogenic Th17 cells in vivo. Since, we have further identified key transcriptional and epigenetic mechanisms associated with this pathway, indicating that innate-like signaling drives signature programming events that render Th17 cells altogether more pathogenic for autoimmune inflammation. Our preliminary work presented herein demonstrates that activation of this pathway amplifies gene-promoting chromatin modifications at Th17-related loci, likely resulting in increased access for pro-inflammatory transcription factors as well as the binding of a novel chromatin regulatory factor. This chromatin regulator was recently characterized by our laboratory and we demonstrate its essentiality in mediating Th17 cell- dependent autoimmune inflammation. Finally, our data demonstrates that endogenous ligands are potent amplifiers of this pathway as well as encephalitogenicity in Th17 cells. Taken together, these novel results suggest that autoimmune disorders may be treated through targeting the downstream effects of this pathway to inhibit Th17 cells. Therefore, the goal of these studies is to characterize the mechanisms responsible for the increased inflammatory potential that we have firmly established in these Th17 cells. Transcriptional, epigenetic, and functional analyses will be performed to tease out the contributions of the novel regulatory factors identified by our preliminary work. Consequently, our project is designed to test our central hypothesis through two interlinked specific aims.


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 = $0 )
2025	2023	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE & SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Allergy and Infectious Diseases Research	000	5	10/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE & SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Allergy and Infectious Diseases Research	000	5	11/21/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $390,000 )
2023	2023	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE & SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Allergy and Infectious Diseases Research	000	5	10/18/2022	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2022 ( Subtotal = $390,000 )
2022	2022	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Allergy and Infectious Diseases Research	000	4	10/13/2021	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2021 ( Subtotal = $390,000 )
2021	2021	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Allergy and Infectious Diseases Research	000	3	10/20/2020	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2020 ( Subtotal = $390,000 )
2020	2020	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Allergy and Infectious Diseases Research	000	2	11/7/2019	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2019 ( Subtotal = $390,000 )
2019	2019	ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE	3333 GREEN BAY RD	NORTH CHICAGO	IL	60064	LAKE	USA	Allergy and Infectious Diseases Research	000	1	11/15/2018	NEW	$390,000
														Subtotal = $390,000

Grand Total All Awards = $1,950,000

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Molecular regulation of TLR2-mediated autoimmune inflammation

Award Number: R01AI141596

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 11/15/2018

PERIOD OF PERFORMANCE END DATE: 10/31/2025

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