# Dysregulated Polyamine Metabolism in H. pylori-associated Gastric Inflammation and Disease Progression

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2021 · —

## Abstract

Helicobacter pylori infection of the stomach and the resulting clinical consequences of chronic gastritis, peptic
ulcer disease, and disease progression to gastric cancer remains a major health concern for Veterans. This
pathogen infects half of the world’s population, and gastric cancer is the third leading cause of cancer deaths
worldwide. H. pylori prevalence in Veterans is high; deployment-related infection is a problem, especially
acquisition of strains associated with higher risk for carcinogenesis. The three polyamines, putrescine (Put),
spermidine (Spd), and spermine (Spm), are ubiquitous molecules with many biological effects. Put is synthesized
by the rate-limiting enzyme, ornithine decarboxylase (ODC), and is converted sequentially to Spd and Spm,
which is back-converted to Spd by spermine oxidase (SMOX). Our Lab has had a long interest in the role of
polyamines in GI inflammation and carcinogenesis, and we have the following exciting findings pertinent to this
renewal grant: 1) Smox–/– mice infected with H. pylori exhibit decreased gastric inflammation, DNA damage, and
chemokine expression, associated with depletion of Spd; 2) These phenotypes are recapitulated in H. pylori-
infected 2D organoids from Smox–/– mice; 3) A new link between the H. pylori-induced pro-carcinogenic activation
of b-catenin and SMOX, including findings that Smox–/– mice and gerbils treated with a SMOX inhibitor have loss
of b-catenin activation in vivo; 4) Use of human gastric organoid cultures to demonstrate the effectiveness of a
novel and potent SMOX inhibitor in blocking H. pylori-induced b-catenin activation, associated with Spd
depletion; 5) Implication of a unique form of protein translation, hypusination, via the action of deoxyhypusine
synthase (DHPS), a process which has been linked to carcinogenesis and appears to be attenuated by Smox
deletion; 6) Demonstration of somatic genomic abnormalities by whole exome sequencing (WES) in gastritis and
dysplasia tissues of INS-GAS mice, a model of H. pylori-induced carcinogenesis. We will now make effective
use of important molecular tools, including valuable mutant mouse models, a key SMOX inhibitor, and advanced
use of 3D and 2D gastric organoids from mice and VA patients. We hypothesize that dysregulated polyamine
metabolism, due to SMOX and associated generation of Spd and hypusination, provides a molecular
pathway leading to risk for gastric disease progression to carcinogenesis. Our specific aims are: 1) To
directly determine the role of SMOX and Spd in gastric carcinogenesis. We will test: A) The effect of SMOX in
cancer-prone INS-GAS mice, analyzing H. pylori-induced carcinogenesis, DNA damage, b-catenin activation,
and GEC function in FVB/N INS-GAS Smox–/– mice +/- Spd; B) A novel, potent, second-generation SMOX
inhibitor, SLH150-54, in INS-GAS mice and gerbils; C) The effect of SMOX/Spd on the formation of somatic
genomic abnormalities using whole exome sequencing. 2) To determine if epithelial DHPS...

## Key facts

- **NIH application ID:** 10196972
- **Project number:** 5I01CX002171-02
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Keith T. Wilson
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10196972

## Citation

> US National Institutes of Health, RePORTER application 10196972, Dysregulated Polyamine Metabolism in H. pylori-associated Gastric Inflammation and Disease Progression (5I01CX002171-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10196972. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*