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A Novel Role for PTPN2 in Intestinal Epithelial Barrier Regulation

Award Number: R01DK091281
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: 04/05/2012
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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A Novel Role for PTPN2 in Intestinal Epithelial Barrier Regulation - SUMMARY/ABSTRACT Compromised intestinal barrier function and alterations in intestinal microbes are critical factors contributing to many autoinflammatory diseases such as Inflammatory Bowel Disease (IBD), celiac disease and Type 1 diabetes, and affect ~24 million Americans (www.niehs.nih.gov). Genetic contributions to these diseases include the increased association with loss-of-function single-nucleotide polymorphisms (SNPs) in the protein tyrosine phosphatase non-receptor type 2 (PTPN2) gene. Moreover, PTPN2 was identified as a major influence on microbiome composition across multiple patient cohorts.In mice constitutively lacking Ptpn2, we identified substantial changes in gut microbiota populations highlighted by increased abundance of a novel mouse adherent-invasive E. coli (AIEC). This mouse AIEC was able to colonize mouse intestine, exacerbate colitis onset, and delay recovery from colitis. Moreover, we now report that PTPN2 loss compromises Paneth cells which have critical roles in preserving intestinal mucosal-microbial homeostasis. We also identify that epithelial PTPN2 deletion reduces Paneth cell antimicrobial peptide expression, and increases susceptibility to pathogen infection. Thus, we hypothesize that PTPN2 serves as a “microbial modulator” by regulating innate defense mechanisms of epithelial cells to protect the intestine against bacterial ‘dysbiosis’, including expansion of, and colonization with, the disease-relevant pathobiont, AIEC. The goals of this proposal are to determine how loss of PTPN2 activity disrupts i) Paneth cell antimicrobial properties; and ii) how does PTPN2 regulate other (non-Paneth cell) features of epithelial antimicrobial defense and intracellular bacterial handling. Expected Outcomes & Impact: This proposal will increase our broader understanding of the molecular basis by which host factors preserve the intestinal barrier and microbial homeostasis, and lead to development of new approaches and targets to restore host-microbe relationships in diseases such as IBD.


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 = $523,224 )
2026	2026	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	12	5/28/2026	NON-COMPETING CONTINUATION	$523,224
														Subtotal = $523,224

Issue Date FY: 2025 ( Subtotal = $549,223 )
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	11	7/16/2025	NON-COMPETING CONTINUATION	$549,223
														Subtotal = $549,223

Issue Date FY: 2024 ( Subtotal = $620,460 )
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	10	5/15/2024	NON-COMPETING CONTINUATION	$536,713
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	001	10	7/10/2024	SUPPLEMENT FOR EXPANSION	$83,747
														Subtotal = $620,460

Issue Date FY: 2023 ( Subtotal = $681,286 )
2023	2023	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	9	8/10/2023	COMPETING CONTINUATION	$596,461
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	9	9/7/2023	SUPPLEMENT FOR EXPANSION	$84,833
2023	2020	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	8	12/5/2022	NON-COMPETING CONTINUATION	-$8
														Subtotal = $681,286

Issue Date FY: 2020 ( Subtotal = $418,399 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	6/3/2020	NON-COMPETING CONTINUATION	$418,399
														Subtotal = $418,399

Issue Date FY: 2019 ( Subtotal = $433,422 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	7	7/2/2019	NON-COMPETING CONTINUATION	$433,414
2019	2017	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	3/20/2019	COMPETING CONTINUATION	$8
														Subtotal = $433,422

Issue Date FY: 2018 ( Subtotal = $477,574 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	6/28/2018	NON-COMPETING CONTINUATION	$477,574
														Subtotal = $477,574

Issue Date FY: 2017 ( Subtotal = $502,816 )
2017	2017	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/19/2017	COMPETING CONTINUATION	$502,824
2017	2015	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	7/20/2017	NON-COMPETING CONTINUATION	-$8
														Subtotal = $502,816

Issue Date FY: 2015 ( Subtotal = $330,600 )
2015	2015	REGENTS, UNIVERSITY OF CALIFORNIA	POST OFFICE BOX 112	RIVERSIDE	CA	92521	RIVERSIDE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/24/2015	NON-COMPETING CONTINUATION	$330,600
														Subtotal = $330,600

Issue Date FY: 2014 ( Subtotal = $330,600 )
2014	2014	REGENTS, UNIVERSITY OF CALIFORNIA	POST OFFICE BOX 112	RIVERSIDE	CA	92521	RIVERSIDE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/24/2014	NON-COMPETING CONTINUATION	$330,600
														Subtotal = $330,600

Issue Date FY: 2013 ( Subtotal = $319,030 )
2013	2013	REGENTS, UNIVERSITY OF CALIFORNIA	POST OFFICE BOX 112	RIVERSIDE	CA	92521	RIVERSIDE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	7/9/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$319,030
2013	2012	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/8/2013	NEW	$0
														Subtotal = $319,030

Issue Date FY: 2012 ( Subtotal = $303,168 )
2012	2012	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/4/2012	NEW	$303,168
														Subtotal = $303,168

Grand Total All Awards = $5,489,802

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A Novel Role for PTPN2 in Intestinal Epithelial Barrier Regulation

Award Number: R01DK091281

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: 04/05/2012

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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