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Inflammatory cascades disrupt Treg function through epigenetic mechanisms

Award Number: R01AI089714
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: 02/10/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Inflammatory cascades disrupt Treg function through epigenetic mechanisms - PROJECT SUMMARY/ABSTRACT CD4+FOXP3+lymphocytes are expanded within the intestinal inflammatory lesion of Crohn’s disease (CD); however, ongoing inflammation belies presumed anti-inflammatory function of this cell. FOXP3 is required for differentiation and function of T regulatory (TREG) cells. FOXP3-mediated gene repression is lost in intestinal T cells of CD patients. Indeed, “FOXP3+ Crohn’s cell (FOXP3+CD)” bears a transcriptional signal more closely related to the pro-inflammatory TH17 cell. Derivation, function, and therapeutic implications of the FOXP3+CD cell remain poorly understood. Our long-term goal is to dissect epigenetic mechanisms regulating TREG cellular differentiation and function in the setting of GI inflammation. Consequently, the objective is to identify mechanisms responsible for activation of the TH17 phenotypic transcriptional network within intestinal FOXP3+CD cells and test therapeutic opportunities to restore their regulatory function in vivo. Our central hypothesis is that a shared chromatin configuration between TREG and TH17 cells allows for rapid activation of a TH17-like pro-inflammatory gene program in intestinal FOXP3+TREG cells. A set of TH17-relevant genes are accessible, yet not active in human TREG cells. A defining feature of the TH17 program was significant enrichment of CCCTC binding factor (CTCF) motifs. CTCF, a well-known topologically-associated domain (TAD) insulator protein, also mediates intra-TAD chromosomal looping and enhancer-promoter interaction regulating gene transcription. Bioinformatic analysis of this TH17 program indicates an inhibitory role for Polycomb Repressor Complex 1 (PRC1). Deletion of PRC1 in murine FOXP3+ cells led to secretion of prototypic TH17-like cytokines in FOXP3+ cells, and spontaneous colitis. The rationale is that with mechanistic insight into the biology of intestinal TREG cell in inflammation, one can apply targeted FOXP3+ CD cell-directed therapy including engineering of human TREG cells for adoptive cell therapy trials. To test the central hypothesis and obtain the overall objective we will address the following three questions: Aim1: Why are CTCF motifs associated with the TH17 program? Aim2: Why are TH17-associated genes accessible yet not active in TREG cells? Aim3: Why do FOXP3+CD cells express prototypic TH17 cytokines? Upon conclusion, we will understand the epigenetic pathways and 3D chromatin architecture spawning the FOXP3+CD cell and mechanisms shaping their development and function. This contribution is significant as the FOXP3+CD cell is expanded in the Crohn’s lesion, phenocopies TH17 cell which is implicated in Crohn’s disease (and other inflammatory diseases), and represents an important epigenetic drug target for systemic or re-engineered cellular therapy. There is general acknowledgement of risk of FOXP3+ TREG cells converting to pathogenic FOXP3+TH17-like cells upon adoptive transfer in Crohn’s trials; yet, this project is the first to articulate both signature and precise epigenetic events that regulate activation of the TH17 program in TREG cells.


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 = $505,712 )
2025	2025	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Allergy and Infectious Diseases Research	002	16	5/19/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$505,712
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	15	12/20/2024	NON-COMPETING CONTINUATION	$464,261
2025	2025	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Allergy and Infectious Diseases Research	004	16	6/4/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$159,158
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	001	15	5/19/2025	NON-COMPETING CONTINUATION	-$464,261
2025	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	003	14	6/4/2025	NON-COMPETING CONTINUATION	-$159,158
														Subtotal = $505,712

Issue Date FY: 2024 ( Subtotal = $477,611 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	14	1/4/2024	NON-COMPETING CONTINUATION	$429,850
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	001	14	5/24/2024	NON-COMPETING CONTINUATION	$47,761
														Subtotal = $477,611

Issue Date FY: 2023 ( Subtotal = $498,524 )
2023	2023	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	13	1/12/2023	NON-COMPETING CONTINUATION	$498,524
														Subtotal = $498,524

Issue Date FY: 2022 ( Subtotal = $492,611 )
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	12	1/25/2022	NON-COMPETING CONTINUATION	$492,611
														Subtotal = $492,611

Issue Date FY: 2021 ( Subtotal = $477,000 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	11	2/10/2021	COMPETING CONTINUATION	$477,000
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	002	11	9/28/2021	COMPETING CONTINUATION	$18,114
2021	2020	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	001	10	9/28/2021	NON-COMPETING CONTINUATION	-$18,114
														Subtotal = $477,000

Issue Date FY: 2020 ( Subtotal = $423,934 )
2020	2020	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	10	1/17/2020	NON-COMPETING CONTINUATION	$423,934
														Subtotal = $423,934

Issue Date FY: 2019 ( Subtotal = $465,711 )
2019	2019	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	9	1/18/2019	NON-COMPETING CONTINUATION	$465,711
														Subtotal = $465,711

Issue Date FY: 2018 ( Subtotal = $439,277 )
2018	2018	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	001	8	6/28/2018	SUPPLEMENT FOR EXPANSION	$41,777
2018	2018	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	8	1/9/2018	NON-COMPETING CONTINUATION	$397,500
														Subtotal = $439,277

Issue Date FY: 2017 ( Subtotal = $397,500 )
2017	2017	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	7	1/12/2017	NON-COMPETING CONTINUATION	$397,500
														Subtotal = $397,500

Issue Date FY: 2016 ( Subtotal = $397,500 )
2016	2016	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	6	1/12/2016	COMPETING CONTINUATION	$397,500
														Subtotal = $397,500

Issue Date FY: 2015 ( Subtotal = $394,250 )
2015	2015	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	5	1/1/2015	NON-COMPETING CONTINUATION	$394,250
														Subtotal = $394,250

Issue Date FY: 2014 ( Subtotal = $394,250 )
2014	2014	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	4	1/22/2014	NON-COMPETING CONTINUATION	$354,825
2014	2014	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	001	4	6/6/2014	NON-COMPETING CONTINUATION	$39,425
														Subtotal = $394,250

Issue Date FY: 2013 ( Subtotal = $370,595 )
2013	2013	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	001	3	5/30/2013	NON-COMPETING CONTINUATION	$15,770
2013	2013	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	3	1/14/2013	NON-COMPETING CONTINUATION	$354,825
														Subtotal = $370,595

Issue Date FY: 2012 ( Subtotal = $394,250 )
2012	2012	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	2	2/9/2012	NON-COMPETING CONTINUATION	$394,250
														Subtotal = $394,250

Issue Date FY: 2011 ( Subtotal = $197,125 )
2011	2011	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	1	2/4/2011	NEW	$197,125
														Subtotal = $197,125

Grand Total All Awards = $6,325,850

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Inflammatory cascades disrupt Treg function through epigenetic mechanisms

Award Number: R01AI089714

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: 02/10/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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