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TL1A Regulation of Group 3 Innate Lymphoid Cells in Colitis

Award Number: R01DK120985
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/10/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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TL1A Regulation of Group 3 Innate Lymphoid Cells in Colitis - Inflammatory bowel disease (IBD) affects millions of people worldwide, causing significant morbidity. Despite improvements in medical therapy, nearly one-third of IBD patients develop refractory disease requiring hospitalization or surgery. The long-term goal of this proposal is to identify the cellular and molecular mechanisms underlying disease in order to design targeted therapies that are safer and more effective. Group 3 innate lymphoid cells (ILC3s) play a central role in the pathophysiology of IBD. As the major producers of IL- 22, ILC3s play a critical role in promoting mucosal healing in IBD2. Emerging data, however, has revealed that ILC3s can function as a double-edged sword, driving tissue inflammation in mouse models of colitis and IBD. In addition to these innate effector functions, recent studies have revealed that MHCII+ RORt+ ILCs can act as antigen presenting cells (APCs) which limit T cell responses against commensal bacteria and promote regulatory T cells. The objective of this proposal is to define the molecular and cellular mechanisms that regulate these heterogenous functions of ILCs in IBD. Our published and preliminary data identify TNF-like cytokine 1A (TL1A) as central regulator of these heterogenous function of ILC3s. TL1A is highly expressed in human colonic tissue during IBD and variants in TNFSF15, the genetic locus that encodes TL1A, confer higher risk for more aggressive disease complications. While early studies showed a pathogenic role for TL1A in driving inflammatory T cell responses, subsequent work from our own group and others have revealed a direct role for TL1A in regulating ILCs. Using RNA-seq of TL1A-stimulated intestinal ILC3, our preliminary data reveal that TL1A signaling robustly and specifically induce expression of the transcription factor Bhlhe40. Bhlhe40 is a member of the basic helix- loop-helix TF family, which is a key regulator of cytokine production by macrophages and T cells. Bhlhe40 is required for inflammation and promotes immune responses in autoimmunity, transplantation, and cancer. Single cell data identified Bhlhe40 in intestinal ILCs, but the potential role of Bhlhe40 in ILC3 is unknown. Using new genetic mouse models and human biopsy samples, this proposal will test the hypothesis that Bhlhe40 in ILC3s is critical in shaping innate immunity to in inflammatory colitis as well as coordinating mucosal cellular responses to maintain antigen specific tolerance in the intestine. The expected outcomes of these aims are to identify a new role for Bhlhe40 in shaping innate effector functions of ILC3s and revealing a central role for intestinal ILC3s in coordinating cellular immunity to enforce intestinal tolerance. If successful, these findings will uncover new mechanistic targets for regulating ILC3s in IBD.


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 = $668,149 )
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	5/4/2026	NON-COMPETING CONTINUATION	$668,149
														Subtotal = $668,149

Issue Date FY: 2025 ( Subtotal = $694,632 )
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	5	7/2/2025	COMPETING CONTINUATION	$695,365
2025	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/24/2025	NON-COMPETING CONTINUATION	-$733
2025	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	2/5/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $694,632

Issue Date FY: 2023 ( Subtotal = $381,375 )
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/17/2023	NON-COMPETING CONTINUATION	$381,375
														Subtotal = $381,375

Issue Date FY: 2022 ( Subtotal = $381,375 )
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/10/2022	NON-COMPETING CONTINUATION	$343,238
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	3/24/2022	NON-COMPETING CONTINUATION	$38,137
														Subtotal = $381,375

Issue Date FY: 2021 ( Subtotal = $381,375 )
2021	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/22/2021	NON-COMPETING CONTINUATION	$381,375
														Subtotal = $381,375

Issue Date FY: 2020 ( Subtotal = $381,375 )
2020	2020	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/7/2020	NEW	$381,375
														Subtotal = $381,375

Grand Total All Awards = $2,888,281

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TL1A Regulation of Group 3 Innate Lymphoid Cells in Colitis

Award Number: R01DK120985

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/10/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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