# Deciphering the Molecular Genetics of VSIG10L in Barrett's Neoplasia

> **NIH NIH P01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $507,720

## Abstract

PROJECT SUMMARY/ABSTRACT
The etiology of Barrett's esophagus (BE), a molecularly complex disorder of the distal esophagus, remains
elusive. Patients with BE are at an increased risk of developing esophageal adenocarcinoma (EAC), a lethal,
increasingly prevalent, and the most common esophageal malignancy in the U.S. Our long-term objective is to
identify the causative mechanisms underlying the onset and malignant progression of BE, and to develop
evidence-based biomarkers and chemopreventive/therapeutic strategies for subsequent clinical implementation.
Project 1 of this program is based on our prior discovery of a novel germline susceptibility mutation in VSIG10L
(S631G) that modulates the epithelial integrity of squamous epithelium. VSIG10L is expressed in suprabasal
cells as squamous epithelium matures. Furthermore, we have generated mice that are either null for Vsig10l or
carry the mouse ortholog of the human S631G variant. Homozygous Vsig10l knockout (KO) and homozygous
S631G knockin (KI) mice are both viable. Electron microscopy imaging demonstrates decreased desmosomal
cell to cell junctions in the suprabasal squamous cells of mice with altered VSIG10L. Further, both mouse
genotypes initially develop multilayered epithelium at 12 months of age and BE like metaplasia by 24 months at
the squamo-columnar junction (SCj) upon exposure to genotoxic/oxidative stress (Deoxycholate). The three
Aims of Project 1 strategically address how mutations in VSIG10L lead to a susceptibility to BE. Aim 1 will define
phenotypic and molecular alterations affected by VSIG10L mutations in three dimensional organotypic cultures.
Aim 2 will define phenotype of our mouse models and identify molecular alterations that lead to BE like
metaplasia and dysplasia. Aim 3 studies how VSIG10L expression is associated with a susceptibility to develop
BE in human subjects. Collectively, our proposed studies will delineate the role of VSIG10L in esophageal
homeostasis, uncovering novel mechanisms of BE-EAC pathogenesis.

## Key facts

- **NIH application ID:** 10932156
- **Project number:** 5P01CA269019-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** AMITABH CHAK
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $507,720
- **Award type:** 5
- **Project period:** 2023-09-20 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932156

## Citation

> US National Institutes of Health, RePORTER application 10932156, Deciphering the Molecular Genetics of VSIG10L in Barrett's Neoplasia (5P01CA269019-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10932156. Licensed CC0.

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