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Exploring Glutamate Carboxypeptidase II (GCPII) Dysregulation in Human and Experimental IBD

Award Number: K01OD030517
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Exploring Glutamate Carboxypeptidase II (GCPII) Dysregulation in Human and Experimental IBD - PROJECT SUMMARY/ABSTRACT This K01 SERCA award will provide protected research time and mentoring to Diane Peters, DVM, MS, PhD as she establishes an independent biomedical research career. Dual-trained as a veterinarian and pharmacologist, Dr. Peters has a strong background in comparative medicine, animal models of human disease, in vivo pharmacology, and protease biology. Through completion of the training and research aims outlined in this proposal, she will expand her knowledge of inflammatory bowel disease (IBD) and build an advanced technical skill set, to include immunofluorescent imaging, CRISPR/Cas9 genome editing and gastrointestinal phenotyping methods, that will form a solid foundation for her planned independent research program. IBD is a chronic condition that negatively impacts patient quality of life and is associated with a high public health burden. There is no cure for IBD and a large percentage of affected individuals are unresponsive to all available treatments. Glutamate carboxypeptidase II (GCPII) is zinc metallopeptidase that is highly overexpressed in the two main subtypes of IBD: Crohn's disease and ulcerative colitis. The promise of GCPII as a therapeutic target in IBD has been demonstrated in multiple independent preclinical studies, which have shown that small molecule GCPII inhibitors have significant anti-colitis activity in three mechanistically-distinct mouse models. While it is apparent that GCPII upregulation is relevant in both human and mouse IBD, knowledge gaps exist regarding its function in disease. This K01 SERCA research will yield critical new data relevant to the biology of GCPII in IBD. Specifically, in Aim #1 GCPII expression will be defined in normal and IBD-affected gastrointestinal tissues of human and mouse IBD. In Aim #2, a novel knock-in mouse will be generated that overexpresses human GCPII in the ileum and colon, followed by longitudinal characterization of barrier function, gastrointestinal inflammation, microbiome composition and visceral pain response. It is hypothesized that the localization of GCPII overexpression will be conserved in human and mouse IBD and that adult mice with forced ileum and colon GCPII overexpression will spontaneously develop colitis. Successful completion of these research aims will (1) increase our understanding of GCPII dysregulation in IBD, (2) identify GCPII+ target cell populations with relevance to ongoing to drug development efforts and (3) yield a novel mouse model of IBD that may have increased similarity to human disease. The proposed research will be supervised by a multidisciplinary team of expert scientists and clinicians including: Dr. Barbara Slusher, Director of Johns Hopkins Drug Discovery, Dr. Pankaj Jay Pasricha, Director of the Johns Hopkins Center for Neurogastroenterology, Dr. Cynthia Sears, Director of the Johns Hopkins Germ Free Murine Core, Dr. Robert Anders, Gastrointestinal Pathologist, Dr. Christine McDonald, expert in Gastrointestinal Barrier Function, and Dr. Thaddeus Stappenbeck, Gastrointestinal Pathologist and expert in Mucosal Immunity, who are well-suited to mentor Dr. Diane Peters in her translational IBD research career.


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 = $130,140 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Research Infrastructure Programs	001	5	4/10/2026	NON-COMPETING CONTINUATION	$58,730
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Research Infrastructure Programs	000	5	2/18/2026	NON-COMPETING CONTINUATION	$71,410
														Subtotal = $130,140

Issue Date FY: 2025 ( Subtotal = $130,140 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Research Infrastructure Programs	001	4	7/22/2025	NON-COMPETING CONTINUATION	$13,014
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Research Infrastructure Programs	000	4	12/16/2024	NON-COMPETING CONTINUATION	$117,126
														Subtotal = $130,140

Issue Date FY: 2024 ( Subtotal = $130,140 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Research Infrastructure Programs	001	3	5/17/2024	NON-COMPETING CONTINUATION	$13,014
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Research Infrastructure Programs	000	3	12/8/2023	NON-COMPETING CONTINUATION	$117,126
														Subtotal = $130,140

Issue Date FY: 2023 ( Subtotal = $130,140 )
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Research Infrastructure Programs	000	2	12/17/2022	NON-COMPETING CONTINUATION	$130,140
														Subtotal = $130,140

Issue Date FY: 2022 ( Subtotal = $130,140 )
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Research Infrastructure Programs	001	1	6/28/2022	NEW	$13,013
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Research Infrastructure Programs	000	1	12/27/2021	NEW	$117,127
														Subtotal = $130,140

Grand Total All Awards = $650,700

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Exploring Glutamate Carboxypeptidase II (GCPII) Dysregulation in Human and Experimental IBD

Award Number: K01OD030517

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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