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Targeted Identification of IBD Risk Gene Variant Impact on Immune-Epithelial Crosstalk and Intestinal Barrier Function

Award Number: R01DK138456
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2024
PERIOD OF PERFORMANCE END DATE: 02/28/2028

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Targeted Identification of IBD Risk Gene Variant Impact on Immune-Epithelial Crosstalk and Intestinal Barrier Function - Project Summary Single nucleotide polymorphisms (SNPs) in the protein tyrosine phosphatase N2 (PTPN2) gene are confirmed risk markers in both forms of inflammatory bowel disease (IBD), Crohn’s disease (CD) and ulcerative colitis (UC). PTPN2 loss-of-function variants reduce PTPN2 activity and are associated with more severe disease in IBD patients. While we and others have utilized PTPN2 knockdown and knockout models to generate preliminary insights into the potential contributions of PTPN2 loss-of- function in IBD development, there is very little information as to how PTPN2 clinical variants compromise intestinal homeostasis. A major contributor to this knowledge gap lies in the lack of suitable model systems to study PTPN2 variants in intestinal epithelial cells, the critical cell type that comprises the gut barrier. To address this, we propose to utilize IBDGC resources to 1) identify gene clustering, expression, and biological pathways altered in IBD patients carrying the PTPN2 rs1893217 loss-of- function variant; 2) generate novel in vitro models that will allow us to mechanistically probe key targets, perform challenge and rescue (using pharmacologic and genetic approaches) experiments; and 3) generate novel gut-on-chip models to integrate these findings into a more physiologically relevant experimental system. Outcomes & Impact: This proposal will capitalize on our expertise in studying roles of PTPN2 in multiple facets of IBD pathophysiology by utilizing the unique resources of IBDGC to develop cutting- edge models for a greater translational understanding of how PTPN2 variants contribute to IBD. These models will also represent a significant advance to the field for discovery biology and for future ‘personalized’ drug development studies.


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 = $420,894 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	6/11/2025	NON-COMPETING CONTINUATION	$42,089
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/20/2025	NON-COMPETING CONTINUATION	$378,805
														Subtotal = $420,894

Issue Date FY: 2024 ( Subtotal = $444,809 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/23/2024	NEW	$444,809
														Subtotal = $444,809

Grand Total All Awards = $865,703

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Targeted Identification of IBD Risk Gene Variant Impact on Immune-Epithelial Crosstalk and Intestinal Barrier Function

Award Number: R01DK138456

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2024

PERIOD OF PERFORMANCE END DATE: 02/28/2028

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