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

项目总结 该多重PI R01方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道病理中的作用。我们 假设NRF2-ACSS2轴参与酒精相关食道的代谢重编程 病理学。我们将使用人类细胞和转基因小鼠通过三个步骤来验证这一假设 独立和互补的具体目标。在目标1中，我们将描述NRF2-ACSS2轴在 介导人食道鳞状上皮细胞酒精诱导的代谢重编程。在……里面 目的2，我们将验证NRF2-ACSS2轴在酒精诱导的代谢中的作用 在小鼠体内的食道重编程。在目标3中，我们将检查NRF2和NRF2的抑制作用 ACSS2抑制剂对酒精诱导的代谢重编程和体内食道病理的影响。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 抑制作为一种预防酒精相关性食道病变的新机制 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.