Tuesday, July 1, 2025 7/1/2025

Characterization of Mucosal Lymphocytes

Award Number: R01DK044319
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: 09/30/1992
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Characterization of Mucosal Lymphocytes - PROJECT SUMMARY/ABSTRACT CD1d-restricted, invariant natural killer T cells (iNKT) cells play a critical role in regulating the commensal microbiota and resistance to mucosal pathogens. Conversely, iNKT cell levels are suppressed by microbiota in early (pre-weaned), but not later (post-weaned), life. If critical microbial signals are not provided during early life, colonic iNKT cell levels remain elevated leading to increased susceptibility to colitis in later-life. Recently, we discovered that colon iNKT cells are resident cells that establish themselves in early life in a pathway controlled locally by macrophages within a developmental program regulated by specific microbial factors. The current research proposal addresses the unanswered question about how macrophages and thiazole-oxazole modified microcins (TOMMs) associated with Escherichia coli regulate intestinal iNKT cells in early life. Our long-term goals are to parse out specific mechanisms and consequences of host-microbial interactions in regulating intes- tinal iNKT cells and in turn how iNKT cells regulate commensalism, pathogenic exposures and colitis. The ob- jective of this research is to better understand the pathways that regulate iNKT cells in early life. Our central hypothesis is that intestinal iNKT cells are resident cells established in early life and under the control of macro- phages and specific microbial factors which determines later life susceptibility to enteric diseases. Specifically, it is proposed that microbes regulate embryonic macrophages in colon which determines the colonic receptivity to early life entry and proliferation of thymic iNKT cell emigrants through cognate and non-cognate mechanisms. We also hypothesize that E. coli expressing TOMMs determine a unique form of colonization resistance in early life that involves impeding iNKT cell residency. The rationale for our proposed research is that developing such insights and the consequences they have for later life susceptibility to enteric diseases will have important impli- cations for processes associated with colonization resistance and immune tolerance. Our central hypothesis will be tested with three specific aims: 1) define the role of fetal macrophages in early life regulation of colon iNKT cell residency; 2) define the sources and mechanisms of the cognate signals that regulate establishment of CD1d-restricted iNKT cell residency, and; 3) define bacterial-derived oxazoles as a regulator of early life iNKT cell development in intestines. In Aim 1 we will show how iNKT cells establish residency in the colon in early life through the activities of embryonic macrophages and the role played by the commensal microbiota. Aim 2 will investigate how CD1d on intestinal macrophages regulate local iNKT cell levels during this critical period of development. Finally, Aim 3 will reveal how a specific microbial factor derived from TOMMs regulate intestinal iNKT cell levels and their control of commensalism in early life. Overall, this proposal is significant because it will demonstrate that iNKT cells are resident cells that are under the control of a developmental process which is regulated and in turn regulates the microbiota and as such provides new opportunities for potentially manipulat- ing these processes in a preventative manner.


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 = $666,550 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	33	6/27/2025	NON-COMPETING CONTINUATION	$666,550
2025	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	31	5/29/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $666,550

Issue Date FY: 2024 ( Subtotal = $666,550 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	32	6/25/2024	COMPETING CONTINUATION	$666,550
2024	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	31	6/17/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $666,550

Issue Date FY: 2023 ( Subtotal = $692,573 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	31	7/13/2023	NON-COMPETING CONTINUATION	$692,573
														Subtotal = $692,573

Issue Date FY: 2022 ( Subtotal = $692,573 )
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	30	6/15/2022	NON-COMPETING CONTINUATION	$692,573
														Subtotal = $692,573

Issue Date FY: 2021 ( Subtotal = $692,573 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	29	6/16/2021	NON-COMPETING CONTINUATION	$692,573
2021	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	27	6/14/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $692,573

Issue Date FY: 2020 ( Subtotal = $692,573 )
2020	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	28	9/17/2020	COMPETING CONTINUATION	$692,573
2020	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	27	9/17/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $692,573

Issue Date FY: 2019 ( Subtotal = $695,335 )
2019	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	27	6/12/2019	NON-COMPETING CONTINUATION	$695,335
														Subtotal = $695,335

Issue Date FY: 2018 ( Subtotal = $697,056 )
2018	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	26	5/18/2018	NON-COMPETING CONTINUATION	$697,056
														Subtotal = $697,056

Issue Date FY: 2017 ( Subtotal = $688,564 )
2017	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	25	4/24/2017	NON-COMPETING CONTINUATION	$619,708
2017	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	25	6/16/2017	NON-COMPETING CONTINUATION	$68,856
														Subtotal = $688,564

Issue Date FY: 2016 ( Subtotal = $688,631 )
2016	2016	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	24	4/21/2016	NON-COMPETING CONTINUATION	$688,631
														Subtotal = $688,631

Issue Date FY: 2015 ( Subtotal = $697,012 )
2015	2015	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	23	4/9/2015	COMPETING CONTINUATION	$697,012
														Subtotal = $697,012

Issue Date FY: 2008 ( Subtotal = $678,846 )
2008	2008	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	16	4/22/2008	NON-COMPETING CONTINUATION	$678,846
														Subtotal = $678,846

Issue Date FY: 2007 ( Subtotal = $675,717 )
2007	2007	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	15	4/23/2007	NON-COMPETING CONTINUATION	$675,717
														Subtotal = $675,717

Issue Date FY: 2006 ( Subtotal = $678,640 )
2006	2006	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	14	5/12/2006	NON-COMPETING CONTINUATION	$678,640
														Subtotal = $678,640

Issue Date FY: 2005 ( Subtotal = $675,210 )
2005	2005	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	13	5/9/2005	COMPETING CONTINUATION	$675,210
														Subtotal = $675,210

Issue Date FY: 2004 ( Subtotal = $456,854 )
2004	2004	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	12	11/21/2003	NON-COMPETING CONTINUATION	$456,854
														Subtotal = $456,854

Issue Date FY: 2003 ( Subtotal = $446,516 )
2003	2003	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	11		NON-COMPETING CONTINUATION	$446,516
														Subtotal = $446,516

Issue Date FY: 2002 ( Subtotal = $436,480 )
2002	2002	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	10	11/5/2001	NON-COMPETING CONTINUATION	$436,480
														Subtotal = $436,480

Issue Date FY: 2001 ( Subtotal = $426,326 )
2001	2001	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	9	4/4/2001	NON-COMPETING CONTINUATION	$426,326
														Subtotal = $426,326

Issue Date FY: 2000 ( Subtotal = $413,909 )
2000	2000	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	8	2/28/2000	COMPETING CONTINUATION	$413,909
														Subtotal = $413,909

Issue Date FY: 1998 ( Subtotal = $353,634 )
1998	1998	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	7	9/10/1998	NON-COMPETING CONTINUATION	$353,634
														Subtotal = $353,634

Grand Total All Awards = $12,812,122

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Characterization of Mucosal Lymphocytes

Award Number: R01DK044319

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: 09/30/1992

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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