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IL1 as a Driver of Mucosal Immune Dysregulation in Inflammatory Bowel Disease

Award Number: K08DK131321
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/10/2022
PERIOD OF PERFORMANCE END DATE: 02/04/2027

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IL1 as a Driver of Mucosal Immune Dysregulation in Inflammatory Bowel Disease - Project Summary/Abstract Inflammatory bowel disease (IBD), consisting of Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory condition affecting the human intestine associated with significant morbidity and limited therapeutic options. Based on the current understanding of IBD pathogenesis, mucosal inflammation seems to arise from a dysregulated crosstalk between intestinal microbes and poorly understood host immune, genetic, and environmental factors. Current biologic therapies available for IBD target specific cytokines (e.g. TNF, IL12/23) or trafficking receptors but a substantial proportion of patients either lose response to, or have disease refractory to, these therapies. There is an urgent need to improve our understanding of IBD pathogenesis to fuel the discovery of additional therapeutic targets. Based on previous investigations, interleukin-1 (IL1) and its associated cytokine family may play a critical role in IBD pathogenesis. IL10 receptor (IL10R)-deficiency, a monogenic form of CD-like IBD leading to colitis and perianal disease within the first year of life, is characterized by enhanced IL1 production in macrophages in both patients and mice. Blockade of IL1 signaling reduces the severity of colitis in IL10R-deficient mice, and several IL10R-deficient patients have been successfully treated with anti-IL1 therapy as a bridge to curative stem cell transplantation. Deep mucosal and peripheral immunophenotyping of a large cohort of IBD and non- IBD subjects using mass cytometry (CyTOF) (Mitsialis et al, Gastroenterology, 2020) has demonstrated that active IBD, especially CD, is characterized by enhanced IL1 expression in specific myeloid populations. Although anti-IL1 therapy is not currently used in the treatment of IBD, this data has led to the hypothesis that there may be subsets of IBD patients with IL1-mediated inflammation, similar to IL10R-deficient patients, whose disease may be amenable to anti-IL1 therapy. This project aims test this hypothesis by specifically interrogating IL1-related transcriptomic and proteomic signatures in IBD. The aims of this project are to (1) define IL1-associated cellular populations in human intestinal mucosa and blood using single cell analyses (CyTOF and scRNA-seq), and (2) determine how these IL1-associated populations differ in IBD, non-IBD, and IL10R-deficient subjects, thereby enabling characterization of IBD phenotypes associated with an enhanced IL1 signature. It is anticipated that IBD patients with an enhanced IL1 signature may share transcriptomic/proteomic findings with IL10R-deficient patients and be defined by a common clinical disease phenotype such as stricturing, fistulizing, or otherwise severe disease. The hope is that the results of this work will guide and set the stage for anti-IL1 therapeutics 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 = $168,400 )
2026	2026	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	3/10/2026	NON-COMPETING CONTINUATION	$168,400
														Subtotal = $168,400

Issue Date FY: 2025 ( Subtotal = $244,000 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	8/19/2025	SUPPLEMENT FOR EXPANSION	$75,600
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/19/2025	NON-COMPETING CONTINUATION	$168,400
														Subtotal = $244,000

Issue Date FY: 2024 ( Subtotal = $168,400 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/26/2024	NON-COMPETING CONTINUATION	$168,400
														Subtotal = $168,400

Issue Date FY: 2023 ( Subtotal = $168,400 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/6/2023	NON-COMPETING CONTINUATION	$168,400
														Subtotal = $168,400

Issue Date FY: 2022 ( Subtotal = $169,900 )
2022	2022	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	8/26/2022	NEW	$0
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	1	1/7/2022	NEW	$169,900
														Subtotal = $169,900

Grand Total All Awards = $919,100

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IL1 as a Driver of Mucosal Immune Dysregulation in Inflammatory Bowel Disease

Award Number: K08DK131321

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/10/2022

PERIOD OF PERFORMANCE END DATE: 02/04/2027

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