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Deciphering the Molecular Genetics of VSIG10L in Barrett's Neoplasia

破译巴雷特瘤形成中 VSIG10L 的分子遗传学

基本信息

批准号：
10713939
负责人：
AMITABH CHAK
金额：
$ 54.97万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-20 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10713939
关键词：
3-Dimensional Ablation Acceleration Address Affect Age Months Barrett Esophagus Barrett&apos s carcinogenesis Barrett&apos s neoplasia Biological Assay Biological Markers Biopsy Cell-Cell Adhesion Cells Chemopreventive Agent Complement 3d Complex Desmosomes Development Disease Distal Duct (organ) structure Dysplasia Electron Microscopy Ephrin-B2 Epithelium Esophageal Adenocarcinoma Esophageal injury Esophageal mucous membrane Esophagus Etiology Exhibits Exposure to Family Functional disorder Genes Genetic Genotype Germ-Line Mutation Gland Goals Homeostasis Human Impairment Inflammation Inherited Injury Intercellular Junctions Interleukin-1 beta Knock-in Knock-in Mouse Knock-out Knockout Mice Lead Lesion Malignant - descriptor Malignant Neoplasms Metaplasia Methods Modeling Molecular Molecular Genetics Morphology Mucous Membrane Mus Mutant Strains Mice Mutation Organoids Orthologous Gene Oxidative Stress Pathogenesis Pathology Pathway interactions Patients Phenotype Phosphotransferases Pilot Projects Predisposition Recurrence Reflux Risk Role Signal Transduction Squamous Cell Squamous Differentiation Squamous Epithelium Submucosa Testing Therapeutic Tissues United States Variant cancer prevention carcinogenesis clinical implementation comparison control deoxycholate design evidence base exome sequencing experimental study follow-up genotoxicity healing human subject indexing induced pluripotent stem cell injury and repair interstitial microscopic imaging mouse model mutant novel prevent programs prospective segregation synergism transcriptomic profiling transdifferentiation translational goal wound healing

项目摘要

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.

项目总结/文摘