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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：
9897450
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/9897450
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 Epithelium 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 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 experimental study human disease in vivo innovation insight keratinocyte mitochondrial dysfunction neoplastic novel parkin gene/protein premalignant problem drinker 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.

项目摘要食管鳞状细胞癌（ESCC）是所有人类鳞状细胞癌中最致命的，酒精是主要的危险因素。酒精在食管上皮细胞损伤及食管鳞癌中的作用病理生物学仍然未知。乙醇代谢产生乙醛，一种主要的人类致癌物质。在饮酒可能引起疾病的靶器官中，食管是独特的，因为它直接与胃肠道相连。暴露在高浓度乙醇和乙醛中酒精解毒包括清除乙醛通过醛脱氢酶2（Aldh 2），分解醛的线粒体酶。 Aldh 2功能障碍增加具有多态性Aldh 2突变（Aldh 2 E487 K）的个体的癌症风险。在Aldh 2-/- 和Aldh 2 E487 K突变小鼠和Aldh 2缺失的人食管上皮细胞，酒精诱导线粒体损伤和氧化应激，DNA加合物形成和DNA损伤增加，这表明线粒体功能障碍和活性氧（ROS）可能有助于遗传 Aldh 2功能失调的食管上皮细胞的不稳定性。酒精诱导的氧化应激通过自噬，一种细胞保护机制，其去除受损的细胞成分，包括功能障碍的细胞成分，线粒体此外，酒精刺激ESCC肿瘤生长，增加肿瘤起始细胞的表达，高自噬和高CD 44表达（CD 44 H）。长期目标是识别食管粘膜防御机制，可用于预防或治疗ESCC。在这方面的总体目标这项研究旨在阐明酒精如何影响具有Aldh 2功能障碍的食管上皮细胞。这项建议利用基因工程小鼠模型、患者的活检、具有改变的Aldh 2状态的人类细胞系， CRISPR/Cas9方法、异种移植物系列移植试验和新型3D食管类器官系统与乙醇暴露和药物干预作为一个全面的平台，以确定 Aldh 2在上皮对酒精暴露反应中的机制和功能作用。核心假设是 Aldh 2限制酒精诱导的线粒体功能障碍，抑制氧化应激和ESCC肿瘤启动和成长。这一假设是根据2004年产生的强有力的初步数据提出的。申请人的实验室，并将通过以下三个相互关联的具体目标进行测试：（1）阐明线粒体Aldh 2如何限制酒精诱导的食管上皮细胞损伤;（2）确定如何自噬减少酒精诱导的线粒体损伤和氧化应激;（3）确定Aldh 2 影响酒精诱导的食管肿瘤特征。这些创新的研究将揭示新的 Aldh 2在酒精诱导的氧化应激和食管上皮细胞中的作用损伤以及自噬介导的细胞保护在ESCC和其他酒精性疾病的发病机制中的作用，良性和恶性都有。