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: 10810414
• 负责人: XIAOXIN Luke CHEN
• 金额: $ 57.33万
• 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/10810414
• 关键词: NRF2; ACSS2; Axis; Alcohol; induced

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.

项目概要 这个多重 PI R01 提案旨在结合体外和体内方法来阐明 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 轴介导酒精相关食管的代谢重编程 病理。我们将使用人类细胞和转基因小鼠通过三个方面来测试这一假设 独立且互补的具体目标。在目标 1 中，我们将描述 NRF2-ACSS2 轴在 介导体外人食管鳞状上皮细胞中酒精诱导的代谢重编程。在 目标 2，我们将验证 NRF2-ACSS2 轴在介导酒精诱导的代谢中的作用 小鼠食道体内重编程。在目标 3 中，我们将检查 NRF2 和 ACSS2 抑制剂对酒精诱导的体内代谢重编程和食管病理学的影响。如果 如果假设被证明是正确的，这些研究将为NRF2/ACSS2奠定坚实的机制基础 抑制作为一种新的基于机制的预防酒精相关食管病理的措施 将来。