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Immune regulation of intestinal health and disease

Award Number: R01AI123368
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: 04/01/2016
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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Immune regulation of intestinal health and disease - PROJECT ABSTRACT The gastrointestinal tract is colonized with trillions of normally beneficial microbes, termed the microbiota, that are essential for human health. However, the pathogenesis of numerous infectious, inflammatory, and metabolic diseases involves a loss of immunologic tolerance to the gut microbiota. This has been demonstrated robustly in basic, translational, and clinical studies of inflammatory bowel disease (IBD). The fundamental focus of our proposed renewal for R01AI123368 is to build on recent paradigm-shifting results from the first funding cycle that detailed a novel pathway that is essential to orchestrate immune tolerance to gut microbiota and restrain intestinal inflammation. Specifically, our prior studies detailed how group 3 innate lymphoid cells (ILC3s) present microbiota-derived antigens to CD4 T cells on MHCII, instruct the differentiation of a unique form of RORgt+ regulatory T cells (Tregs), and prevent spontaneous intestinal inflammation. Further, we find that these cellular interactions are dysregulated in the inflamed intestine of individuals with IBD (see Zhou et al., Nature, 2022 and Lyu et al., Nature, 2022 as the most recent examples). We generated new preliminary data to support this renewal application where we propose to mechanistically advance this paradigm and will explore the therapeutic potential of our key findings. This includes three specific aims, which will: (i) define how ILC3s sense microbiota to initiative antigen presentation, (ii) elucidate key molecular determinants endowing a tolerogenic program in MHCII+ ILC3s, and (iii) identify whether MHCII+ ILC3s can be harnessed to enforce tolerance to diverse microbes or restrain gut inflammation as a pre-clinical therapy. We will employ basic mouse models, as well as translate our findings into human specimens. This research is directly relevant to IBD and many other chronic inflammatory diseases where disruptions to immune tolerance underlie disease pathogenesis, and it is expected that our mechanistic results will provoke new opportunities for preventative, therapeutic or curative treatment strategies.


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 = $493,244 )
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Allergy and Infectious Diseases Research	000	7	10/29/2024	NON-COMPETING CONTINUATION	$493,244
														Subtotal = $493,244

Issue Date FY: 2024 ( Subtotal = $508,500 )
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Allergy and Infectious Diseases Research	001	6	9/4/2024	COMPETING CONTINUATION	$50,850
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	6	11/16/2023	COMPETING CONTINUATION	$457,650
														Subtotal = $508,500

Issue Date FY: 2023 ( Subtotal = -$3,006 )
2023	2020	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	5	6/20/2023	NON-COMPETING CONTINUATION	-$3,006
														Subtotal = -$3,006

Issue Date FY: 2020 ( Subtotal = $423,750 )
2020	2020	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	5	3/12/2020	NON-COMPETING CONTINUATION	$423,750
														Subtotal = $423,750

Issue Date FY: 2019 ( Subtotal = $423,750 )
2019	2019	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	4	3/14/2019	NON-COMPETING CONTINUATION	$423,750
														Subtotal = $423,750

Issue Date FY: 2018 ( Subtotal = $423,750 )
2018	2018	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	3	3/14/2018	NON-COMPETING CONTINUATION	$423,750
														Subtotal = $423,750

Issue Date FY: 2017 ( Subtotal = $423,750 )
2017	2017	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	2	3/30/2017	NON-COMPETING CONTINUATION	$423,750
														Subtotal = $423,750

Issue Date FY: 2016 ( Subtotal = $423,750 )
2016	2016	CORNELL UNIVERSITY, MEDICAL COLLEGE	1300 YORK AVENUE, S 217	NEW YORK-NEW YORK	NY	10021		USA	Allergy and Infectious Diseases Research	000	1	3/29/2016	NEW	$423,750
														Subtotal = $423,750

Grand Total All Awards = $3,117,488

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Immune regulation of intestinal health and disease

Award Number: R01AI123368

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: 04/01/2016

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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