# Wnt Pathway Regulation of Gastric Stem Cell Function

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $509,150

## Abstract

PROJECT SUMMARY
This resubmission of a new R01 application proposes to define mechanisms of gastric stem cell regulation,
investigating the role of Wnt signaling to maintain tissue homeostasis and to promote epithelial cell proliferation
in the stomach. Our proposed studies are directly relevant to human disease, focusing on mechanisms of
gastric polyp formation in patients with familial adenomatous polyposis (FAP). FAP is a genetic disorder
resulting from germline APC gene mutations that dysregulate Wnt signaling, with extreme gastrointestinal (GI)
proliferative disease resulting from Wnt promotion of stem cell proliferation. Although Wnt is well known to
regulate GI stem cells, questions remain regarding sensitivity to Wnt dysregulation in different regions of the GI
tract. Colonic manifestations in FAP patients are extreme, with aggressive disease characterized by early
adenoma and cancer development, which commonly leads to colectomy at a young age. The consequences of
Wnt dysregulation in gastric stem cells is less well understood, although polyp, adenoma and cancer
development are enhanced in the FAP patient stomach. Notably, almost all FAP patients exhibit frequent
hyperproliferative polyps localized to the proximal fundic/corpus region of the stomach, while, in contrast, the
distal antral/pylorus region of the stomach is relatively spared from these polyps and develops more occasional
adenomatous growths. The basis for the regional effect of FAP mutations on corpus vs. antral stem cells and
gastric tissue responses is unknown. To address this important question, this project focuses on defining Wnt
regulation of gastric stem cells to uncover the differential effects of pathway activation in the proximal vs. distal
stomach. We will pursue the mechanisms of FAP polyp formation in the stomach by functional and genetic
analysis of gastric polyp and non-polyp organoids and tissues from a biobank of human FAP gastric tissue
samples that will be built as a component of this study. Human FAP organoid studies will be complemented by
mouse genetic, pharmacologic and organoid models to gain deeper mechanistic insight into regional Wnt
regulation of gastric stem cells. The studies are framed by the “Just Right Hypothesis” which defines
differential sensitivities along the GI tract based on region-specific stem cell responses to different levels of
Wnt activation. Together the proposed studies will determine how dysregulated Wnt signaling leads to
differential gastric epithelial cell proliferation and polyp formation in proximal vs. distal stomach. This
information will establish a scientific framework to help define the gastric manifestations in FAP patients. In
addition, the studies will provide functional insights to develop a deeper understanding of Wnt pathway
regulation of gastrointestinal stem cells. Furthermore, understanding mechanisms of Wnt pathway regulation of
gastric stem cell function is important to refine strategies to propagate adult...

## Key facts

- **NIH application ID:** 10364859
- **Project number:** 1R01DK126451-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** LINDA C. SAMUELSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $509,150
- **Award type:** 1
- **Project period:** 2022-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364859

## Citation

> US National Institutes of Health, RePORTER application 10364859, Wnt Pathway Regulation of Gastric Stem Cell Function (1R01DK126451-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10364859. Licensed CC0.

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