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Aldh2 and mitochondrial homeostasis in esophageal pathobiology

食管病理学中的 Aldh2 和线粒体稳态

基本信息

批准号：
10383155
负责人：
Hiroshi Nakagawa
金额：
$ 36.45万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10383155
关键词：
3-Dimensional Acetaldehyde Affect Agonist Alcohol consumption Alcohols Aldehydes Antioxidants Autophagocytosis Benign Biological Assay Biological Models Biology Biopsy CD44 gene CRISPR/Cas technology Carcinogens Cell Line Cells Characteristics Chloroquine Coupled Cytoprotection DNA DNA Adduction DNA Damage Data Defense Mechanisms Dependence Development Diet Disease Drug Metabolic Detoxication Engineering Enzymes Epithelial Epithelial Cells Esophageal Diseases Esophageal Squamous Cell Carcinoma Esophageal mucous membrane Esophagus Ethanol Ethanol Metabolism Exposure to Flow Cytometry Fostering Functional disorder Genetic Genetically Engineered Mouse Goals Homeostasis Human Human Cell Line Human Pathology Immunodeficient Mouse Impairment Individual Injury Intervention Isoenzymes Knowledge Laboratories Lesion Liquid substance Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Mediating Metabolism Mission Mitochondria Mus Mutant Strains Mice Mutation Organ Organoids Oxidative Stress Oxides Parkin Pathogenesis Pathogenicity Pathology Patients Pharmacology Prevention Protein Isoforms Public Health Publishing Quality Control Reactive Oxygen Species Reporter Research Risk Factors Role Squamous Epithelium Squamous cell carcinoma Structure System Testing Transplantation United States National Institutes of Health Validation Vesicle Wild Type Mouse Xenograft procedure alcohol exposure alcohol pharmacology alcohol response aldehyde dehydrogenases cancer risk cell growth cell injury dietary control experimental study human disease in vivo innovation insight keratinocyte mitochondrial dysfunction neoplastic novel premalignant problem drinker translational applications tumor tumor growth tumor initiation

项目摘要

PROJECT SUMMARY Esophageal squamous cell carcinoma (ESCC) is the deadliest of all human squamous cell carcinomas with alcohol as a major risk factor. The role of alcohol (ethanol) in the esophageal epithelial cell injury and ESCC pathobiology remains unknown. Ethanol metabolism produces acetaldehyde, a major human carcinogen. Amongst the target organs alcohol drinking may cause diseases, esophagus is unique because it is directly exposed to high concentrations of EtOH and acetaldehyde. Alcohol detoxification involves clearance of acetaldehyde via aldehyde dehydrogenase 2 (Aldh2), the mitochondrial enzyme which breaks down aldehydes. Aldh2 dysfunction increases cancer risk in individuals with polymorphic Aldh2 mutation (Aldh2E487K). In Aldh2-/- and Aldh2E487K mutant mice and Aldh2-depleted human esophageal epithelial cells, alcohol induces mitochondrial damage and oxidative stress with increased DNA adducts formation and DNA damage, suggesting that mitochondrial dysfunction and reactive oxygen species (ROS) may contribute to genetic instability in Aldh2 dysfunctional esophageal epithelial cells. Alcohol-induced oxidative stress is alleviated by autophagy, a cytoprotective mechanism which removes damaged cellular components including dysfunctional mitochondria. Moreover, alcohol stimulates ESCC tumor growth with increased tumor-initiating cells displaying high autophagy and high CD44 expression (CD44H). The long-term goal is to identify esophageal mucosal defense mechanisms that can be manipulated for prevention or therapy of ESCC. The overall objective in this proposal is to clarify how alcohol affects esophageal epithelial cells with Aldh2 dysfunction. This proposal utilizes genetically engineered mouse models, patients' biopsies, human cell lines with altered Aldh2 status via the CRISPR/Cas9-approach, xenograft serial transplantation assays and a novel 3D esophageal organoid system with ethanol exposure and pharmacological interventions as a comprehensive platform to define the mechanistic and functional role of Aldh2 in epithelial response to alcohol exposure. The central hypothesis is that Aldh2 limits alcohol-induced mitochondrial dysfunction, suppressing oxidative stress and ESCC tumor initiation and growth. This hypothesis has been formulated on the basis of strong preliminary data produced in the applicant's laboratory and will be tested by pursuing the following three interrelated Specific Aims: (1) To clarify how mitochondrial Aldh2 limits alcohol-induced esophageal epithelial cell injury; (2) To define how autophagy reduces alcohol-induced mitochondrial damage and oxidative stress; (3) To determine how Aldh2 influences alcohol-induced esophageal neoplastic characteristics. These innovative studies will reveal novel insight into the role of dysfunctional Aldh2 in alcohol-induced oxidative stress and esophageal epithelial cell injury as well as autophagy-mediated cytoprotection in the pathogenesis of ESCC and other alcoholic diseases, both benign and malignant.

项目总结