Thursday, August 21, 2025 8/21/2025

Unraveling the Role of NADPH Oxidase in Inflammation-associated Pancreatic Diseases

Award Number: R01DK123079
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: 09/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2026

Group Awards By:

View Award Description

Unraveling the Role of NADPH Oxidase in Inflammation-associated Pancreatic Diseases - Abstract Pancreatic inflammation is the major cause of gastrointestinal-related clinical morbidity and mortality, and effective therapeutic strategies against pancreatic inflammatory diseases remain an unmet medical need. Inflammation is a common feature in the pathogenesis of pancreatitis and associated acinar-to-ductal metaplasia (ADM), pancreatic intraepithelial neoplasia (PanIN) lesions, and pancreatic ductal adenocarcinoma (PDAC). Given the prominent role of inflammation in the spectrum of pancreatic pathologies, understanding pancreas- specific inflammatory mechanisms is critical for the prevention and treatment of the associated diseases. Inflammation is known to induce reactive oxygen species (ROS). Among known causal factors, ROS act as both a signaling molecule and a mediator of inflammation. Wild-type KRAS is subject to ROS modification on cysteine of the redox-sensitive NKC118D motif leading to a transient hyperactivation. KRAS mutants are observed in ~30% of patients with chronic pancreatitis, suggesting the critical role of KRAS mutations in pancreatic inflammation. In the past thirty years, mutant KRAS has been viewed as being locked in a constitutively active state. However, recent studies have found that mutant KRAS, at an endogenous level, is not constitutively active but can be hyper-activated by inflammatory insults leading to sustained inflammation, irreversible ADM, and PanIN lesions. However, the molecular mediator and mechanism linking inflammation to mutant KRAS hyperactivation and associated pathologies remain elusive. Studies have shown that NADPH oxidases (NOXs) are a major mediator of pancreatitis-induced inflammation and major enzymes activated by mutant KRAS for the generation of ROS. However, whether mutant KRAS is subject to the same ROS modification as wild-type KRAS leading to the observed hyperactivity in the context of inflammation is unknown. The objective of this proposal is to identify the molecular mediator and unravel the underlying mechanism on how inflammation promotes mutant KRAS hyperactivation and associated pancreatic pathologies. Notably, by ablating the NOX-docking subunit p22phox in mice expressing an endogenous level of KRASG12D/+ in pancreatic acinar cells, we demonstrate that NOX inhibition considerably curbs KRASG12D/+ hyperactivation, suggesting that NOX is not only a downstream effector but also a potential upstream regulator of KRASG12D. Thus, NOX and KRASG12D potentially form a co-activation feed-forward loop necessary to induce chronic inflammation, irreversible ADM, and PanIN lesions. We hypothesize that under inflammation, NOX generates ROS to modify the redox-sensitive motif of KRASG12D, leading to KRASG12D hyperactivation and associated pathologies. Our hypothesis will be tested with three specific aims in mouse models in the context of inflammatory insults. Aim 1 is to determine the role of NOX in pancreatic inflammation. Aim 2 is to determine if NOX is necessary for KRASG12D hyperactivation, sustained inflammation, irreversible ADM, and PanIN lesions. Aim 3 is to determine if the redox-sensitive NKC118D motif is required for KRASG12D hyperactivation and associated pathologies. Information gained in our studies will fill the outstanding knowledge gap on how inflammatory insults promote mutant KRAS hyperactivation and associated pathologies and guide the design of novel preventive and therapeutic strategies against these diseases in humans.


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 = $0 )
2025	2024	THE UNIVERSITY OF TEXAS AT EL PASO	500 W UNIVERSITY AVE	EL PASO	TX	79968	EL PASO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	5	5/2/2025	NON-COMPETING CONTINUATION	$0
2025	2022	THE UNIVERSITY OF TEXAS AT EL PASO	500 W UNIVERSITY AVE	EL PASO	TX	79968	EL PASO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	1/13/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$46,593
2025	2022	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	1/13/2025	NON-COMPETING CONTINUATION	-$1
2025	2021	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/13/2025	NON-COMPETING CONTINUATION	-$46,592
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $331,560 )
2024	2024	THE UNIVERSITY OF TEXAS AT EL PASO	500 W UNIVERSITY AVE	EL PASO	TX	79968	EL PASO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/16/2024	NON-COMPETING CONTINUATION	$331,560
														Subtotal = $331,560

Issue Date FY: 2023 ( Subtotal = -$10,530 )
2023	2022	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/14/2023	NON-COMPETING CONTINUATION	-$355,905
2023	2022	UNIVERSITY OF TEXAS AT EL PASO	500 W UNIVERSITY AVE	EL PASO	TX	79968	EL PASO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	5/10/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2022	UNIVERSITY OF TEXAS AT EL PASO	500 W UNIVERSITY AVE	EL PASO	TX	79968	EL PASO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	2/14/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$345,375
														Subtotal = -$10,530

Issue Date FY: 2022 ( Subtotal = $366,493 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/27/2022	NON-COMPETING CONTINUATION	$355,906
2022	2020	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	11/26/2021	NEW	$10,587
														Subtotal = $366,493

Issue Date FY: 2021 ( Subtotal = $355,906 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/7/2021	NON-COMPETING CONTINUATION	$355,906
2021	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	5/7/2021	NEW	-$13,049
2021	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/11/2021	NEW	$13,049
														Subtotal = $355,906

Issue Date FY: 2020 ( Subtotal = $355,906 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/8/2020	NEW	$355,906
														Subtotal = $355,906

Grand Total All Awards = $1,399,335

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Unraveling the Role of NADPH Oxidase in Inflammation-associated Pancreatic Diseases

Award Number: R01DK123079

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: 09/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer