# Adminstrative equipment supplement for 5R16GM149389-02:Role of Protein Kinase A (PKA)-mediated mesenchymal-epithelial crosstalk in gastric preneoplasia

> **NIH NIH R16** · TUSKEGEE UNIVERSITY · 2024 · $99,650

## Abstract

Project Summary
According to the American Society of Clinical Oncology, in the year 2020, stomach cancer caused death of
768,793 patients worldwide making it the fourth leading cause of cancer deaths. H. pylori infection is the
strongest risk factor for gastric cancer. H. pylori-initiated inflammation leads to atrophic gastritis, spasmolytic
polypeptide expressing metaplasia (SPEM), gastric intestinal metaplasia (GIM) and dysplasia, a series of
preneoplastic lesions strongly associated with gastric cancer. The eradication of H. pylori by antibiotic treatment
has been effective in reducing the incidence of preneoplastic lesions and gastric cancer. However, following H.
pylori eradication already established mucosal metaplastic changes may not reverse, and the risk of gastric
cancer in such patients remains high. A better understanding of the mechanisms contributing to inflammation
and the resulting preneoplastic lesions is required to develop rational and effective therapies. One of the
mechanisms by which H. pylori stimulates inflammatory signaling and preneoplastic lesions is by disrupting the
communication between the gastric epithelium and the surrounding mesenchyme/stroma. We have identified a
novel role of PKA activation in the gastric mesenchyme in establishing a proinflammatory and preneoplastic state
that is associated with downregulation of BMP signaling which is known to be a key regulator of gastric
inflammation and preneoplasia. We generated and characterized a novel conditional mutant mouse Six2Cre+/--
PKAcRfl/wt (CA-PKA) model in which single allele-mediated expression of constitutively active PKA (PKAcR)
was induced in the stomach mesenchyme using Six2-Cre transgenic mice. CA-PKA Mice develop preneoplastic
lesions such as atrophic gastritis, SPEM, GIM and dysplasia along with marked chronic inflammation, factors
strongly associated with gastric cancer The central hypothesis of this proposal is that PKA activation in the gastric
mesenchyme is a key driver of gastric carcinogenesis by inciting inflammation and inhibiting BMP signaling that
will be tested in the following three aims. Aim 1 is to determine the mechanisms that contribute to inflammation
and oxyntic atrophy in CA-PKA mice. Aim 2 is to determine the effects of genetic modulation of BMP pathway
inhibitor gremlin 1 (Grem1) on the severity of gastric preneoplastic lesions in CA-PKA mice. Aim 3 is to determine
the impact of misregulated PKA signaling on H. felis-induced gastric pathology. Expected outcomes of the
proposed research will define the molecular and functional significance of mis-regulated PKA signaling in
disrupting gastric homeostasis and driving pathology. A better understanding of misregulated PKA signaling as
an underlying cause of gastric inflammation and preneoplasia can help develop preventative and treatment
strategies for gastric cancer and associated pathological conditions.

## Key facts

- **NIH application ID:** 11032456
- **Project number:** 3R16GM149389-02S1
- **Recipient organization:** TUSKEGEE UNIVERSITY
- **Principal Investigator:** Pawan Puri
- **Activity code:** R16 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $99,650
- **Award type:** 3
- **Project period:** 2023-07-17 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11032456

## Citation

> US National Institutes of Health, RePORTER application 11032456, Adminstrative equipment supplement for 5R16GM149389-02:Role of Protein Kinase A (PKA)-mediated mesenchymal-epithelial crosstalk in gastric preneoplasia (3R16GM149389-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11032456. Licensed CC0.

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