Ethanol-induced Protein Acylation Regulates Metabolism

描述（由申请人提供）：慢性乙醇消耗有助于长期肝损伤，导致酒精性肝病的发生和进展。不幸的是，目前终末期酒精性肝病的预后很差，而且往往无法治疗，这主要是因为致病机制还不清楚。两位早期研究人员的这项研究提案提出了这样的假设：酒精代谢会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，所有这些都会导致线粒体功能障碍。为了验证这一假设，我们提出了完整的蛋白质组学图谱研究，完整的代谢表征，和一系列创新的体内小鼠生理学实验与新的小鼠模型，这将导致更深入地了解线粒体蛋白酰化在酒精代谢过程中的作用。我们实验室的工作将特别关注代谢表征和体内小鼠生理学实验，而Fritz博士的工作将专注于蛋白质组学图谱研究以及体内小鼠生理学实验。在过去的几年里，我们广泛合作绘制线粒体蛋白乙酰组，并开始了解乙酰化在酒精代谢过程中对线粒体功能的作用。我们的初步数据表明，除了乙酰化的变化，丙酰化和琥珀酰化的变化响应酒精代谢。因此，鉴定翻译后修饰的全部谱并了解其对线粒体代谢的影响是了解酒精性肝病进展以及干预和治疗的潜在策略的关键。

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.