Ethanol-induced Protein Acylation Regulates Metabolism

描述（由申请人提供）：慢性乙醇消费会导致长期肝损伤，导致酒精性肝病的发生和发展。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，主要是因为致病机制尚不清楚。两位早期研究者的研究方案提出了酒精代谢诱导线粒体蛋白乙酰化改变的假设，以及其他新发现的翻译后修饰，包括丙酰化和琥珀酰化，都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，全面的代谢表征，以及一系列创新的小鼠体内生理实验，这些实验将使我们更深入地了解线粒体蛋白酰化在酒精代谢中的作用。我们实验室的工作将专注于代谢表征和小鼠体内生理实验，而Fritz博士的工作将专注于蛋白质组学制图研究，以及小鼠体内生理实验。在过去的几年里，我们进行了广泛的合作，绘制了线粒体蛋白乙酰化图谱，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，除了乙酰化的变化外，丙酰化和琥珀酰化也会随着酒精代谢而变化。因此，确定完整的翻译后修饰并了解它们对线粒体代谢的影响是了解酒精性肝病进展和潜在干预和治疗策略的关键。

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.