The role of protein O-GlcNAcylation in liver injury

项目摘要/摘要 肝脏是一个主要的代谢器官，负责在变化中维持全身的动态平衡 环境。鉴于酒精在全球的使用，肥胖症和病毒感染的流行，肝脏损伤 在临床实践中很常见。控制肝细胞寿命和肝细胞寿命平衡的分子机制 慢性肝损伤导致的死亡在很大程度上仍然难以捉摸。O-β-N-乙酰氨基葡萄糖(O-GlcNAc) 修饰已经成为一种重要的调节机制，支持正常的肝脏生理和 代谢性疾病。这种普遍和动态的翻译后修饰由O-GlcNAc控制 转移酶(OGT)和O-GlcNAcase(OGA)。我们最近发现肝脏特异的OGT基因敲除小鼠 肝脏肿大、气球状变性和肝纤维化。因此，我们假设OGT扮演着一个 慢性肝损伤中肝细胞存活和死亡之间的关键分子开关。至 检验这一假设，我们建议承担三个具体目标。目标1将定义OGT在以下方面的角色 肝损伤的发病机制；目标2将确定OGT在肝细胞生存和死亡中的关键靶点 3将确定OGT调节坏死性下垂在肝损伤中的功能重要性。成功 该项目的完成将为OGT在调节平衡方面的作用提供重要的见解 肝细胞存活和死亡与肝损伤的发生。肝脏特异性OGT的详细研究 基因敲除小鼠可能会建立一种有用的小鼠模型，概括人类肝损伤的特征，以及 促进慢性肝病防治的治疗靶点识别。

Project Summary/Abstract The liver is a major metabolic organ responsible for maintaining whole-body homeostasis in a changing environment. Given the worldwide use of alcohol, the epidemic of obesity and viral infection, liver damage is common in clinical practice. The molecular mechanisms that control the balance between hepatocyte life and death in response to chronic liver injury remain largely elusive. O-linked β-N-acetylglucosamine (O-GlcNAc) modification has emerged as an important regulatory mechanism underlying normal liver physiology and metabolic disease. This prevalent and dynamic post-translational modification is controlled by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). We recently found that liver-specific OGT knockout mice develop hepatomegaly, ballooning degeneration, and fibrosis in the liver. We therefore hypothesize that OGT acts as a critical molecular switch between hepatocyte survival and death in response to chronic liver injury. To test this hypothesis, we propose to undertake three specific aims. Aim 1 will define the role of OGT in pathogenesis of liver injury; Aim 2 will identify the critical targets of OGT in hepatocyte survival and death; Aim 3 will determine the functional importance of OGT regulation of necroptosis in liver injury. Successful completion of this project will provide critical insights into the role of OGT in regulating the balance between hepatocyte survival and death and the onset of liver injury. Detailed investigation of liver-specific OGT knockout mice will likely establish a useful mouse model that recapitulates features of human liver injury, and facilitate therapeutic target identification for prevention and treatment of chronic liver disease.