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Aging lymphocytes: senescence programs in lymphocytes relevant to human inflammatory bowel disease

Award Number: K08DK134759
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/04/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Aging lymphocytes: senescence programs in lymphocytes relevant to human inflammatory bowel disease - PROJECT SUMMARY/ABSTRACT FOXP3+ CD4+ cells are expanded within the inflamed mucosa of Crohn’s disease (CD) patients; yet the persistence of intestinal inflammation suggests these CD associated CD4+FOXP3+ cells lack typical regulatory T cell (TREG) suppressive function. The functional and therapeutic implications of senescence in FOXP3+ TREG cells is unknown. The long-term goal of this application is to dissect the epigenetic mechanisms driving the differentiation and function of CD4+FOXP3+ cells in the setting of intestinal inflammation. Consequently, the overall objective of this proposal is to identify the mechanisms leading to senescent FOXP3+ cells in the setting of GI inflammation and test therapeutic opportunities to restore regulatory function. The central hypothesis is that CD associated FOXP3+ cells represent a senescent state and contribute to intestinal inflammation. Furthermore, this new cellular phenotype (senescent FOXP3+ cell, snFOXP3) represents a potential therapeutic target. This hypothesis was formulated through single cell transcriptomic analysis of CD4+FOXP3+ cells from the lamina propria of CD patients, produced by this applicant’s laboratory. The rationale is that defining the mechanisms critical to the development and function of snFOXP3 cells in the setting of inflammation will uncover targets for TREG-directed therapies, including the advanced engineering of human TREGS for adoptive cell therapy trials. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Why do FOXP3+ cells become senescent in the absence of BMI1?; 2) Why are FOXP3+ cells senescent in Crohn’s disease?; and 3) Why are snFOXP3 cells proinflammatory? Under the first aim, the applicant will utilize epigenetic assays, which have been established as feasible in the applicant’s hands, to establish BMI1 repression on an ETS1-regulated senescence program in FOXP3+ cells. Antibodies and assay reagents that are already on hand will be used. Under the second aim, the applicant will utilize a biochemistry approach with treatment of cultured TREGS to determine a TNFα-induced disruption of BMI1-mediated repression of senescence. Finally, under the third aim, the applicant will use a novel in vitro co-culture system to establish the proinflammatory capacity of snFOXP3 cells and establish therapeutic targets. The approach is innovative because it departs from the status quo of functional characterization of CD4+FOXP3+ cells utilizing single cell approaches, and a mechanistic approach to define the epigenetic events that lead to a pathogenic snFOXP3 cell. Upon conclusion, the applicant will understand the epigenetic mechanisms leading to the development of snFOXP3 cells in the setting of intestinal inflammation. This contribution is significant as the snFOXP3 is expanded in the Crohn’s lesion, is proinflammatory, and represents an important epigenetic drug target. This project is the first to articulate both signature and precise epigenetic events that regulate activation of senescence in TREGS in intestinal inflammation, therefore advancing the field of therapeutics in engineered cell therapies in the setting of autoimmune diseases.


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 = $163,614 )
2025	2025	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	12/10/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$163,614
2025	2025	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	3	4/2/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$89,657
2025	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/10/2024	NON-COMPETING CONTINUATION	$0
2025	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	4/2/2025	NON-COMPETING CONTINUATION	-$89,657
														Subtotal = $163,614

Issue Date FY: 2024 ( Subtotal = $163,590 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/7/2023	NON-COMPETING CONTINUATION	$163,590
														Subtotal = $163,590

Issue Date FY: 2023 ( Subtotal = $163,620 )
2023	2023	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/4/2023	NEW	$163,620
														Subtotal = $163,620

Grand Total All Awards = $490,824

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Aging lymphocytes: senescence programs in lymphocytes relevant to human inflammatory bowel disease

Award Number: K08DK134759

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/04/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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