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

项目摘要 该多PI R 01提案旨在结合体外和体内方法来阐明 NRF 2-ACSS 2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NRF 2-ACSS 2轴介导酒精相关食管癌的代谢重编程， 病理我们将使用人类细胞和转基因小鼠通过三个实验来验证这一假设。 独立和互补的具体目标。在目标1中，我们将描述NRF 2-ACSS 2轴在以下中的作用： 在体外人食管鳞状上皮细胞中介导酒精诱导的代谢重编程。在 目的2，我们将验证NRF 2-ACSS 2轴在介导酒精诱导的代谢中的作用。 在小鼠食管中的体内重编程。在目标3中，我们将检查NRF 2和NRF 3的抑制作用。 ACSS 2抑制剂对酒精诱导的代谢重编程和体内食管病理学的影响如果 这些研究将为NRF 2/ACSS 2的机理研究奠定坚实的基础 抑制作为一种新基于机制的预防酒精相关食管病变的措施 在未来

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.