Sunday, June 29, 2025 6/29/2025

Investigating gastric inflammation and preneoplastic progression driven by Helicobacter pylori infection

Award Number: R00CA263036
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/07/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

Group Awards By:

View Award Description

Investigating gastric inflammation and preneoplastic progression driven by Helicobacter pylori infection - Project Summary Many cancers are attributed to chronic inflammation, which can cause mutations and activate oncogenic signaling pathways. An important example is gastric cancer, the fourth-leading cause of cancer death worldwide. At least 80% of gastric cancer cases are attributed to stomach infection with the bacterium Helicobacter pylori (Hp), which causes lifelong chronic inflammation that does not eradicate the infection. In some individuals, this inflammation can cause gastric atrophy, metaplasia (conversion of one normal cell type to another), dysplasia (presence of abnormal cells) and finally cancer, but the specific mechanism(s) through which Hp triggers this cascade are not well understood. Similar preneoplastic changes are recapitulated in a mouse model through tamoxifen-induced expression of active KRAS in the chief cells of the stomach (KRAS+ mice). I found that Hp infection of KRAS+ mice exacerbated disease: compared to Hp-KRAS+ mice, Hp+KRAS+ mice had an altered trajectory of metaplasia and accelerated dysplasia. Hp+KRAS+ mice also had expansion of “variant” pit cells (surface mucous cells) that expressed metaplasia- and cancer-related genes like the mucin Muc4. In accordance with the hypothesis that Hp causes cancer through eliciting chronic inflammation, Hp+KRAS+ mice had severe inflammation marked by a ten- fold increase in T cells vs. Hp-KRAS+ mice. In this proposal I will investigate the mechanism(s) through which Hp worsens disease in KRAS+ mice, with a broader goal of better understanding how Hp infection and its associated chronic inflammation cause cancer. I hypothesize that Hp modulates the inflammatory response to prevent Hp eradication from the stomach, and this deleterious immune response leads to metaplasia and dysplasia. In Aim 1 I will perform targeted depletion of CD4+ and CD8α+ T cell subsets to assess whether immune perturbation impacts metaplasia, dysplasia and Hp colonization. I will also assess whether T cells traffic to the stomach in Hp+KRAS+ mice or proliferate locally. Finally, I will test whether Hp+ human samples have increased T cells relative to Hp- samples. In Aim 2 I will investigate candidate Hp virulence factors that modulate inflammation: the cag type IV secretion system and two proteins that modulate T cells, the toxin VacA and the transpeptidase gGT. I will determine whether virulence factor mutants can elicit the same inflammatory and disease progression phenotypes in KRAS+ mice as wild-type Hp does. In Aim 3 I will test whether variant pit cells arise from gastric progenitor cells, and will assess disease phenotypes in Hp+KRAS+MUC4- mice to determine whether Muc4 expression drives pit cell transformation. I will also perform spatial single-cell RNA sequencing in +/- Hp, +/- KRAS mice to discover whether variant pit cells share a gene expression signature with Muc4-expressing cells in the “first gland” of the stomach, a morphologically distinct gland that is believed to be a source of reparative cell lineages. Taken together, the results of these studies will provide new understanding of how Hp infection and inflammation cause gastric preneoplastic progression and may reveal new targets for gastric immunotherapy. These findings may also be applicable to other cancers associated with bacterial infection and/or inflammation, like colorectal cancer.


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 = $122,717 )
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Research Manpower	000	4	1/7/2025	NON-COMPETING CONTINUATION	$97,817
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Research Manpower	002	4	6/16/2025	NON-COMPETING CONTINUATION	$24,900
2025	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Research Manpower	001	3	1/8/2025	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $122,717

Issue Date FY: 2024 ( Subtotal = $375,282 )
2024	2024	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION INC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Cancer Research Manpower	000	3	2/12/2024	EXTENSION WITH OR WITHOUT FUNDS	$231,900
2024	2024	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION INC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Cancer Research Manpower	002	3	9/24/2024	EXTENSION WITH OR WITHOUT FUNDS	$17,100
2024	2024	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION INC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Cancer Research Manpower	001	3	4/23/2024	EXTENSION WITH OR WITHOUT FUNDS	$126,282
														Subtotal = $375,282

Grand Total All Awards = $497,999

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Investigating gastric inflammation and preneoplastic progression driven by Helicobacter pylori infection

Award Number: R00CA263036

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/07/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer