Ethanol-induced Protein Acylation Regulates Metabolism

乙醇诱导的蛋白质酰化调节代谢

• 批准号: 8482109
• 负责人: Kristofer S. Fritz
• 金额: $ 47.47万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-05 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8482109
• 关键词: Acetylation; Acylation; Address; Alcohol consumption; Alcoholic Liver Diseases; Alcoholism; Alcohols; Antibodies; Biological; Cells; Chemicals; Cirrhosis; Computer Simulation; Data; Deacetylase; Diagnostic; Diet; Enzymatic Biochemistry; Enzymes; Ethanol; Ethanol Metabolism; Fatty Liver; Goals; Hepatic; Intervention; Lead; Liver Failure; Liver diseases; Lysine; Maps; Measurement; Measures; Metabolic; Metabolism; Mitochondria; Mitochondrial Proteins; Modeling; Modification; Molecular; Molecular Biology; Mus; Nature; Nutrient; Pathogenesis; Physiology; Play; Post-Translational Protein Processing; Protein Acetylation; Proteins; Proteome; Proteomics; Regulation; Reporting; Research; Research Personnel; Research Proposals; Role; Series; Site; Site-Directed Mutagenesis; Staging; Testing; Therapeutic; Transgenic Mice; United States; Work; alcohol response; base; chronic alcohol ingestion; deprivation; enzyme activity; fatty acid oxidation; feeding; in vivo; innovation; liver injury; meetings; metabolic abnormality assessment; mitochondrial dysfunction; mouse model; novel; outcome forecast; overexpression; prevent; protein structure; public health relevance; research study

DESCRIPTION (provided by applicant): Chronic ethanol consumption contributes to long-term liver damage, resulting in the initiation and progression of alcoholic liver disease. Unfortunately, the current prognosis for end-stage alcoholic liver disease is poor and often untreatable, largely because the pathogenic mechanisms are not well understood. This research proposal by two early stage investigators puts forward the hypothesis that alcohol metabolism induces changes in mitochondrial protein acetylation, and other newly discovered post-translational modifications including propionylation and succinylation, all resulting in mitochondrial dysfunction. To test this hypothesis, we propose complete proteomic mapping studies, full metabolic characterization, and a series of innovative in vivo mouse physiology experiments with novel murine models, which will lead to a deeper understanding of the role of mitochondria protein acylation during alcohol metabolism. The work performed by our lab will focus specifically on the metabolic characterization, and the in vivo mouse physiology experiments, whereas the work performed by Dr. Fritz will focus on the proteomic mapping studies, as well as in vivo mouse physiology experiments. During the past few years, we have collaborated extensively to map the mitochondrial protein acetylome, and begin to understand the role of acetylation on mitochondrial function during alcohol metabolism. Our preliminary data shows that in addition to changes in acetylation, propionylation and succinylation change in response to alcohol metabolism. Thus, identifying the full repertoire of post- translational modifications and understanding their influence on mitochondrial metabolism are key to understanding the progression of alcoholic liver disease and potential strategies for intervention and treatment.

描述（由申请人提供）：慢性乙醇消耗有助于长期肝脏损害，导致酒精性肝病的启动和进展。不幸的是，目前对终阶段酒精性肝病的预后很差，而且通常无法治疗，这主要是因为病原机制尚不清楚。两名早期研究者的这项研究建议提出了以下假说：酒精代谢诱导线粒体蛋白乙酰化的变化，以及其他新发现的翻译后修饰，包括丙酰化和琥珀酰化，所有这些修饰都导致了线粒体功能障碍。为了检验这一假设，我们提出了完整的蛋白质组学研究研究，完整的代谢表征以及具有新型鼠模型的一系列创新的体内小鼠生理学实验，这将使人们对线粒体蛋白酰基在酒精代谢过程中的作用有更深入的了解。我们实验室进行的工作将专门集中于代谢表征，并且体内小鼠生理学实验，而弗里茨博士执行的工作将集中在蛋白质组学映射研究以及体内小鼠生理学实验上。在过去的几年中，我们进行了广泛的合作，以绘制线粒体蛋白乙酰基组，并开始理解乙酰化在酒精代谢过程中乙酰化对线粒体功能的作用。我们的初步数据表明，除了对酒精代谢的响应，乙酰化，丙酰化和琥珀酰化变化外。因此，确定翻译后修饰的全部曲目并理解其对线粒体代谢的影响是了解酒精性肝病的进展以及干预和治疗的潜在策略的关键。