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。