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Regulation of commensal-specific T cells during gastrointestinal inflammation

Award Number: K22AI108719
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/20/2015
PERIOD OF PERFORMANCE END DATE: 07/31/2017

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Regulation of commensal-specific T cells during gastrointestinal inflammation - DESCRIPTION (provided by applicant): The goal of this proposal is to investigate the regulation commensal-specific T cells that become activated as a result of gastrointestinal (GI) infection. The mammalian GI tract contains over 100 trillion bacteria, many of which share properties with overtly inflammatory pathogens. Immune tolerance to the microbiota is important because dysregulated T cell responses to the commensal microbiota are believed to be an important cause of Inflammatory Bowel Disease (IBD). To prevent chronic inflammation, T cell tolerance to commensal-derived antigens is maintained by a structural and immunological barrier, known as the 'mucosal firewall'. A number of environmental factors, including GI infection, can cause a breach in this barrier that leads to activation of long-lived commensal-specific T cells. However, commensal-specific activation after GI infection does not by necessity lead to chronic gastrointestinal enteropathy or IBD and therefore commensal- specific effector/memory T cells are regulated by unknown mechanisms. In addition to causing a breach in the barrier, GI infection also causes significant changes to the microbiota, allowing for the outgrowth of some commensals, such as E. coli, while inducing the loss of others. The potential impact of this infection-induced transformation of the commensal microbiota and it's associated antigens on the T cell response is not known. GI infection also induces the collapse of GI resident T regulatory cells (Tregs) and those Tregs that remain have been shown to induce the expression of transcription factors and cytokines associated with the anti- pathogen 'Th1' effector state. However, the role of antigen in this process and whether Tregs specific to commensal antigens preferentially survive and initiate the Th1 program is not known. Since GI infection does not necessarily lead to chronic GI enteropathy, there must exist mechanisms for the control of commensal-specific T cells post-activation. Aim 1 of this proposal will uncover the regulatory mechanisms that control activated commensal-specific T cells and focuses on three non-exclusive possibilities: 1) reformation of the barrier preventing chronic activation 2) control by Tregs and 3) control by the cytokine interleukin 10. Aim 1 will also address potential consequences of the shift in the microbiota following infection via the creation of novel tools to follow the T cell response to commensal E. coli after GI infection. Aim 2 will address whether commensal-specific Tregs preferentially survive and differentiate to a Th1 state after infection and also whether such 'converted' Tregs survive long-term as a potentially dangerous population of commensal-specific effector T cells. Completion of these aims, along with associated training opportunities associated with this proposal will establish the necessary foundation for my career as an independent investigator.


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: 2018 ( Subtotal = -$20 )
2018	2016	NIAID	6700 B ROCKLEDGE DRIVE	BETHESDA	MD	20817	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	2	11/21/2017	NON-COMPETING CONTINUATION	-$20
														Subtotal = -$20

Issue Date FY: 2016 ( Subtotal = $108,000 )
2016	2016	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	2	7/12/2016	NON-COMPETING CONTINUATION	$108,000
														Subtotal = $108,000

Issue Date FY: 2015 ( Subtotal = $162,000 )
2015	2015	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	1	8/14/2015	NEW	$162,000
														Subtotal = $162,000

Grand Total All Awards = $269,980

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Regulation of commensal-specific T cells during gastrointestinal inflammation

Award Number: K22AI108719

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/20/2015

PERIOD OF PERFORMANCE END DATE: 07/31/2017

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