# Sox4 Dependent Parietal Cell Plasticity in Gastric Ulcer

> **NIH NIH R03** · YALE UNIVERSITY · 2024 · $125,625

## Abstract

PROJECT SUMMARY/ABSTRACT
Gastric ulcer is increasing in the United States due to increasing use of non-steroidal anti-inflammatory drugs
(NSAIDs) and Helicobacter pylori infection. It has been a major cause of gastrointestinal surgery with high
morbidity and mortality. While molecular and cellular mechanisms associated with gastric ulcer repair have been
heavily investigated, information on the cell of origin for regenerated epithelium is limited. Microscopically, gastric
ulcer is characterized by mucosal injuries involving the muscularis mucosae and a cavity surrounded by acute
and chronic inflammation. Numbers of acid secreting parietal cells are decreased in the ulcer edges. Parietal
cells are also decreased in preneoplastic lesions such as atrophic gastritis and Ménétrier’s disease. We have
previously demonstrated that parietal cells undergo apoptosis in an atrophic gastritis mouse model. Ménétrier’s
disease is a rare, acquired, premalignant protein-losing hypertrophic gastropathy induced by EGF receptor
(EGFR) signaling activation. Ménétrier’s disease also shows decreased number of parietal cells, however,
apoptosis is not changed. This raises the possibility that parietal cells transdifferentiate into other cell types rather
than dying in Ménétrier’s disease.
As a part of my K08 project, we examined the fate of parietal cells in a Ménétrier’s disease mouse model and
observed that parietal cells can give rise to other epithelial cell types. Our preliminary data shows that parietal
cells can transdifferentiate into various other epithelial cell types in another EGFR activated condition gastric
ulcer. Preliminary analysis on single cell RNA sequencing (scRNA-seq) comparing normal stomach and gastric
ulcer at day 3 showed upregulated Sox4 expression and activated FoxO signaling pathway in parietal cells from
gastric ulcer. Sox4 and FoxO signaling have been associated with stem cell maintenance, transdifferentiation,
and cancer progression. It has been reported that spasmolytic polypeptide expressing metaplasia (SPEM)
develops at the ulcer edges and plays an important role in gastric ulcer healing. We will investigate if parietal
cells can transdifferentiate into SPEM in gastric ulcer and give rise to other epithelial cell types during gastric
ulcer healing by lineage tracing followed by immunofluorescence microscopy and single cell RNA sequencing.
The role of Sox4 in parietal cell plasticity will also be investigated by knocking out or overexpressing Sox4 in
parietal cells.
Successful completion of the studies proposed in this application will not only provide us with better
understanding of the underlying mechanism of gastric epithelial plasticity but also with a foundation for effective
treatment of gastric ulcer. Also, comparing results from this project with my K08 project will contribute to my long-
term research goal of preventing gastric tumorigenesis and facilitating gastric mucosal regeneration.

## Key facts

- **NIH application ID:** 10987605
- **Project number:** 1R03DK137013-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Won Jae Huh
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $125,625
- **Award type:** 1
- **Project period:** 2024-09-06 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10987605

## Citation

> US National Institutes of Health, RePORTER application 10987605, Sox4 Dependent Parietal Cell Plasticity in Gastric Ulcer (1R03DK137013-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10987605. Licensed CC0.

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