NRF2-ACSS2 Axis in Alcohol-induced Metabolic Reprogramming and Esophageal Pathology

NRF2-ACSS2 轴在酒精诱导的代谢重编程和食管病理学中的作用

基本信息

批准号：
10673201
负责人：
XIAOXIN Luke CHEN
金额：
$ 61.69万
依托单位：
CORIELL INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673201
关键词：
Acetaldehyde Acetates Acetyl Coenzyme A Alcohol consumption Alcohols Animal Model Autoradiography Biological Assay Carbon Carcinogens Cell Proliferation Cell model Cells Citric Acid Cycle Clinical Coenzyme A Ligases Cultured Cells DNA Data Diet Dose Drug Metabolic Detoxication Epithelial Cells Esophageal Diseases Esophageal Squamous Cell Esophageal Squamous Cell Carcinoma Esophagus Ethanol Ethanol Metabolism Family member Foundations Future Gastroesophageal reflux disease Gene Expression Genes Genetic Transcription Genus Hippocampus Histone Acetylation Human Hyperactivity In Vitro Label Link Lipids Liquid substance Malignant Neoplasms Malignant neoplasm of esophagus Measures Mediating Membrane Transport Proteins Metabolic Metabolism Modeling Molecular Mus Neoplasm Metastasis PET/CT scan Pathology Phase Phenotype Preventive Preventive measure Production Proteins Regulation Risk Factors Role Signal Transduction Solid Source Testing Time Tissues Translating Work alcohol exposure alcohol prevention cancer cell density design in vivo inhibitor knock-down lipid biosynthesis metabolomics novel nuclear factor-erythroid 2 stable isotope transcription factor tumor progression uptake

Acetaldehyde Acetates Acetyl Coenzyme A Alcohol consumption Alcohols Animal Model Autoradiography Biological Assay Carbon Carcinogens Cell Proliferation Cell model Cells Citric Acid Cycle Clinical Coenzyme A Ligases Cultured Cells DNA Data Diet Dose Drug Metabolic Detoxication Epithelial Cells Esophageal Diseases Esophageal Squamous Cell Esophageal Squamous Cell Carcinoma Esophagus Ethanol Ethanol Metabolism Family member Foundations Future Gastroesophageal reflux disease Gene Expression Genes Genetic Transcription Genus Hippocampus Histone Acetylation Human Hyperactivity In Vitro Label Link Lipids Liquid substance Malignant Neoplasms Malignant neoplasm of esophagus Measures Mediating Membrane Transport Proteins Metabolic Metabolism Modeling Molecular Mus Neoplasm Metastasis PET/CT scan Pathology Phase Phenotype Preventive Preventive measure Production Proteins Regulation Risk Factors Role Signal Transduction Solid Source Testing Time Tissues Translating Work alcohol exposure alcohol prevention cancer cell density design in vivo inhibitor knock-down lipid biosynthesis metabolomics novel nuclear factor-erythroid 2 stable isotope transcription factor tumor progression uptake

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项目摘要

PROJECT SUMMARY This multiple-PI R01 proposal is designed to incorporate both in vitro and in vivo approaches to elucidate the role of the NRF2-ACSS2 axis in alcohol-induced metabolic reprogramming and esophageal pathology. We hypothesize that the NRF2-ACSS2 axis mediates metabolic reprogramming in alcohol-associated esophageal pathology. We will test this hypothesis using human cells and genetically modified mice through three independent and complementary Specific Aims. In Aim 1, we will characterize the role of NRF2-ACSS2 axis in mediating alcohol-induced metabolic reprogramming in human esophageal squamous epithelial cells in vitro. In Aim 2, we will validate the role of the NRF2-ACSS2 axis in mediating alcohol-induced metabolic reprogramming in mouse esophagus in vivo. In Aim 3, we will examine the inhibitory effects of NRF2 and ACSS2 inhibitors on alcohol-induced metabolic reprogramming and esophageal pathology in vivo. If the hypothesis proved to be true, these studies will lay down a solid mechanistic foundation for NRF2/ACSS2 inhibition as a novel mechanism-based preventive measure against alcohol-associated esophageal pathology in the future.

项目摘要该多个PI R01建议旨在融合体外和体内方法，以阐明该方法 NRF2-ACSS2轴在酒精诱导的代谢重编程和食管病理学中的作用。我们假设NRF2-ACSS2轴介导了酒精相关食管中的代谢重编程病理。我们将使用人类细胞和转基因小鼠通过三个来检验该假设独立和互补的特定目的。在AIM 1中，我们将表征NRF2-ACSS2轴的作用体外介导人食管鳞状上皮细胞中酒精诱导的代谢重编程。在 AIM 2，我们将验证NRF2-ACSS2轴在介导酒精诱导的代谢中的作用在体内重新编程小鼠食道。在AIM 3中，我们将检查NRF2和 ACSS2对酒精诱导的代谢重编程和体内食管病理学的抑制剂。如果是假设被证明是正确的，这些研究将奠定NRF2/ACSS2的固体机械基础抑制作用是一种基于机制的新型预防措施，以针对酒精相关的食管病理学将来。