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

• 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
• 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

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.

项目总结