# The role of gastrin in esophageal submucosal gland acinar ductal metaplasia

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $493,939

## Abstract

Project Summary / Abstract:
Barrett’s esophagus (BE) is a precursor to esophageal adenocarcinoma, a cancer with increasing incidence
and a five-year survival less than 17%. BE and esophageal adenocarcinoma arise in the setting of abnormal
esophageal repair. Our prior work has shown that patients with esophageal injury or BE display acinar ductal
metaplasia within esophageal submucosal glands (ESMGs). Furthermore, using a pig model, we have found
that ESMGs respond to injury with proliferation and a shift to a ductal phenotype with expression of BE
markers. However, the factors that contribute to development of this metaplasia are unknown. Our preliminary
data suggest that metaplasia in ESMGs may be elicited by elevated gastrin exposure as we have identified: 1)
increased expression of the gastrin receptor in the ESMGs and 2) ESMG proliferation in response to gastrin in
vitro. These findings are clinically relevant since proton pump inhibitors (PPIs), which are commonly used for
acid suppression and currently recommended for BE, raise serum gastrin levels. Elevated gastrin levels are
associated with increased risk of metaplasia, dysplasia and cancer in the stomach, colon and pancreas. The
objective of this proposal is to determine the effects of PPIs and elevated gastrin on esophageal proliferation
and metaplasia in ESMGs, the highly specialized submucosal structures that contain esophageal progenitors
and respond to esophageal injury. To accomplish this objective, we will use our novel in vitro and in vivo
porcine models of ESMGs and esophageal repair, and our large cohort of human esophagectomy samples.
Our central hypothesis is that gastrin promotes proliferation, and metaplasia within ESMGS via the gastrin
receptor (CCKBR). We will test the hypothesis that gastrin signaling drives esophageal proliferation and acinar
ductal metaplasia through the gastrin receptor by pursuing three specific aims: 1) Quantify effects of the gastrin
receptor (CCKBR) activation and inhibition on ESMG proliferation and differentiation using in vitro and in vivo
porcine models. 2) Determine the downstream mechanisms between gastrin exposure and acinar ductal
metaplasia. 3) Validate gastrin receptor and signaling targets in human ESMGs and develop ex vivo platforms
to test therapies for acinar ductal metaplasia and BE prevention. Through the proposed aims, we will establish
pre-clinical models to determine the pathological effects of gastrin on ESMG proliferation and induction of
acinar ductal metaplasia. This will be accomplished by characterizing injury-induced changes in gastrin
receptor expression and down-stream signaling effects of gastrin levels found with PPI use. The proposed
aims will address the current debate regarding safety of PPIs and elevated gastrin levels in esophageal
metaplasia and dysplasia and these studies could lead to rapid translation of our findings.

## Key facts

- **NIH application ID:** 10197913
- **Project number:** 5R01DK118022-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Katherine Garman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $493,939
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197913

## Citation

> US National Institutes of Health, RePORTER application 10197913, The role of gastrin in esophageal submucosal gland acinar ductal metaplasia (5R01DK118022-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10197913. Licensed CC0.

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