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Mechanisms of gamma delta intraepithelial lymphocyte-mediated host defense

Award Number: F30DK121391
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/01/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2021

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Mechanisms of gamma delta intraepithelial lymphocyte-mediated host defense - PROJECT SUMMARY/ABSTRACT. The intestinal epithelium is the first line of defense against the trillions of bacteria in the intestinal lumen. Failure to prevent or limit bacterial invasion can lead to infection and may trigger a harmful inflammatory response, as seen in inflammatory bowel disease. Intraepithelial lymphocytes (IEL) expressing the γδ T cell receptor rapidly respond to bacterial translocation through modulation of their migratory behavior and release of soluble host defense factors, including cytokines and antimicrobial peptides (AMP). Though γδ IELs are an essential part of host antibacterial response, many of the processes surrounding γδ IEL-mediated host defense remain unclear. The objective of this application is to elucidate the mechanisms through which γδ IELs contribute to host antibacterial defense. Preliminary data suggests that γδ IEL surveillance behavior and effector function may be partially mediated by cell-autonomous recognition of microbe-associated molecular patterns (MAMP) through Toll-like receptor/MyD88 signaling. Moreover, a newly-identified requirement for γδ IELs in lipopolysaccharide (LPS)-induced epithelial cell shedding may represent a novel form of γδ IEL- mediated host antibacterial defense, as extrusion of enterocytes infected with intracellular bacteria limits pathogen proliferation within the epithelium. These observations have led to the central hypothesis that γδ IELs contribute to host defense against bacterial invasion by activating migratory and effector responses following cell-autonomous MAMP recognition and by promoting the shedding of infected enterocytes. The aims of this application are to 1) determine the contributions of γδ IEL MyD88 signaling to host defense against acute bacterial invasion and 2) determine the mechanisms through which γδ IELs regulate cell shedding in response to acute bacterial challenge. The role of γδ IEL MyD88 in mediating MAMP-induced changes in γδ IEL migration and cytokine/AMP secretion will be assessed using inducible, γδ T-cell-specific MyD88 knockout mice and a combination of in vitro and in vivo approaches. Further, the contribution of γδ IEL MyD88 to antibacterial defense will be determined using Salmonella Typhimurium infections. Next, the mechanisms by which γδ T cells promote LPS-induced epithelial cell shedding will be interrogated by quantifying cell shedding in mice exhibiting altered γδ IEL migratory phenotypes or following γδ TCR inhibition. The requirement for γδ IELs in shedding of Salmonella-infected enterocytes will be assessed at early infection timepoints. Completion of these aims will provide novel insight into the mechanisms driving γδ IEL-mediated antibacterial defense. The results of these studies will contribute towards the long-term goal of determining the therapeutic potential of targeting γδ IEL effector functions as a means to prevent excessive inflammation by promoting rapid clearance of infection. The proposed research and training plan, along with my mentors, advisory committee, and the interdisciplinary environment at my home institution, will help me achieve my long- term career goal of becoming an effective physician-scientist involved in independent translational research.


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: 2023 ( Subtotal = -$48,307 )
2023	2020	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	11/23/2022	NON-COMPETING CONTINUATION	-$42,120
2023	2019	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	11/23/2022	NEW	-$6,187
														Subtotal = -$48,307

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/11/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $42,120 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/17/2020	NON-COMPETING CONTINUATION	$42,120
														Subtotal = $42,120

Issue Date FY: 2019 ( Subtotal = $34,919 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	4/26/2019	NEW	$0
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/26/2019	NEW	$34,919
														Subtotal = $34,919

Grand Total All Awards = $28,732

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Mechanisms of gamma delta intraepithelial lymphocyte-mediated host defense

Award Number: F30DK121391

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/01/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2021

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