# Induction and Evolution of Metaplasia in the Stomach

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $469,692

## Abstract

Atrophic gastritis (parietal cell loss or oxyntic atrophy) is considered the most common precursor to gastric
cancer in humans. Chronic infection with Helicobacter pylori represents the most common cause of atrophy. In
the stomach, metaplasia arises following parietal cell loss. Two types of metaplasia occur in he human
stomach: intestinal metaplasia (the presence of intestinal goblet cell lineages in the stomach) and Spasmolytic
Polypeptide-Expressing Metaplasia or SPEM (the presence of deep antral gland type mucus cells in the
stomach corpus). Investigations over the past decade have led to the recognition that SPEM lineages are
substantially derived from transdifferentiation of protein-secreting chief cells into mucus-secreting metaplastic
lineages. SPEM represents an initial metaplastic response to acute injuries in the stomach. However,
progression of SPEM to more intestinalized and proliferative lineages requires the influence of M2-
macrophages. With chronic inflammation in the stomach, SPEM appears to evolve into intestinal metaplasia.
Our recent investigations have also determined that activation of Ras is critical at all stages of metaplasia
evolution from initial transdifferentiation of SPEM, to promotion of proliferative SPEM, and to emergence of
intestinal metaplasia. Thus, critical extrinsic immune factors and intrinsic epithelial Ras signaling combine to
promote the evolution and expansion of metaplasia in the stomach. We have therefore hypothesized that
immune cell populations drive both the induction of SPEM and the progression of metaplasia. To evaluate this
hypothesis, we will examine two specific aims: First, we will examine the role of intrinsic immune cells (ILC2s)
in the gastric mucosa on the induction of metaplasia. Our previous investigations have implicated a cascade of
IL-33 to IL-13 in the induction of metaplasia in the corpus of the stomach. Since intrinsic immune ILC2s are
thought to represent the major population of cells responsible for secretion of IL-13, we will seek to
characterize the diversity of ILC2s in the stomach and their response to parietal cell loss. We will examine
whether ablation of ILC2s prevents the induction of metaplasia following acute oxyntic atrophy. Finally we will
examine whether IL-13 is a direct activator of transdifferentiation in chief cells. Second, will identify the
immune cell derived factors and intrinsic autocrine epithelial signals that can promote progression of
metaplasia to a more intestinalized and proliferative phenotype. While transdifferentiation of chief cells into
SPEM is an initial transition triggered as a response to parietal cell loss, further progression to more
proliferative and intestinalized metaplasia requires other influences. We have developed metaplastic gastroid
lines from Mist1-KRas mice 1 month or 4 months after induction of active Ras, which display the characteristics
of either SPEM or intestinal metaplasia, respectively. We will utilize these cells to ev...

## Key facts

- **NIH application ID:** 10147046
- **Project number:** 5R01DK101332-08
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** James Richard Goldenring
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $469,692
- **Award type:** 5
- **Project period:** 2014-05-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10147046

## Citation

> US National Institutes of Health, RePORTER application 10147046, Induction and Evolution of Metaplasia in the Stomach (5R01DK101332-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10147046. Licensed CC0.

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