Alcohol Metabolism Disrupts Hepatic Thiol Redox Signaling and Control

酒精代谢破坏肝脏硫醇氧化还原信号和控制

• 批准号: 10585786
• 负责人: Kristofer S. Fritz
• 金额: $ 46.06万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-25 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585786
• 关键词: Acetylation; Alcohol Hepatotoxicity; Alcohol abuse; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; American; Amino Acids; Antioxidants; Area; Aspartate Transaminase; Automobile Driving; Basic Science; Biochemical; Biochemical Pathway; Bioinformatics; Biological Assay; Cessation of life; Chemistry; Chronic; Cirrhosis; Citric Acid Cycle; Clinical; Coenzyme A; Complex; Cysteine; Data; Data Analyses; Data Set; Deacetylase; Development; Ethanol Metabolism; Ethanol toxicity; Fatty-acid synthase; Feedback; Functional disorder; GOT2 gene; Glutathione; Glycolysis; Goals; Healthcare Systems; Hepatic; Hepatocyte; Homeostasis; Hospitalization; Inflammatory Response; Intervention; Investigation; Link; Liver; Liver diseases; Lysine; Metabolic; Modeling; Modification; Morbidity - disease rate; Mus; Oxidants; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Post-Translational Protein Processing; Process; Protein Acetylation; Proteins; Proteome; Proteomics; Recombinant Proteins; Research; Research Project Grants; SIRT1 gene; Signal Transduction; Signaling Protein; Sirtuins; Site; Source; Specificity; Sulfhydryl Compounds; System; TXN gene; Testing; Therapeutic Intervention; Time; United States; Validation; Work; alcohol misuse; aldehyde dehydrogenases; community burden; innovation; lipid metabolism; liver metabolism; mortality; novel; novel therapeutics; overexpression; oxidation; peroxiredoxin; peroxiredoxin 5; protein function; response; statistics; targeted treatment; toxicant

Project Summary Alcohol consumption contributes to approximately 6% of worldwide deaths and is a major cause of morbidity and mortality within the United States. These statistics support a pressing need for understanding the biochemical mechanisms underlying alcohol toxicity and the pathogenesis of alcohol-associated liver disease (ALD). Chronic alcohol metabolism impacts numerous cellular pathways including glycolysis, lipid metabolism, the TCA cycle as well as antioxidant and inflammatory responses. There is a known biochemical link between metabolic alterations, oxidative stress, and protein thiol redox switches (e.g., cysteine (Cys) residues); however, very little information exists regarding how chronic alcohol metabolism impacts hepatic thiol redox signaling and control networks. Our preliminary data supports the notion that alcohol metabolism, protein acetylation, and Cys redox are highly associated. Therefore, we present an innovative approach for investigating how alcohol metabolism impacts thiol redox signaling and control. Central to our aims, the thiol redox proteome is an adaptive interface that provides a means to sense, avoid, and defend against oxidants and other toxicants. Therefore, the hypothesis of this proposal is that alcohol metabolism impacts thiol redox signaling and control through lysine acetylation, resulting in hepatic dyshomeostasis and contributing to ALD. We will investigate the proposed specific aims to test our hypothesis: Specific Aim 1: Characterize altered thiol redox signaling and control due to alcohol metabolism. Specific Aim 2: Utilize Sirtuin 1 overexpression to define mechanisms of acetylation-redox signaling and control. Specific Aim 3: Integrate mechanisms of redox- Cys and acetyl-Lys to elucidate CoAlation specific redox signaling. We will execute these research aims utilizing a cutting-edge proteomics and bioinformatics approach to reveal novel redox sensing mechanisms within hepatocytes. Elucidating how alcohol metabolism alters hepatic redox signaling and control through novel post-translational modifications will support the development of targeted clinical interventions to ameliorate ALD in millions of Americans.

项目摘要 饮酒量约为全球死亡的6％，是发病率的主要原因 和美国境内的死亡率。这些统计数据支持理解 酒精毒性和酒精相关肝病的发病机理的生化机制 （ALD）。慢性酒精代谢会影响许多细胞途径，包括糖酵解，脂质代谢， TCA周期以及抗氧化剂和炎症反应。有一个已知的生化联系 代谢改变，氧化应激和蛋白质硫醇氧化还原开关（例如半胱氨酸（CYS）残基）； 但是，关于慢性酒精代谢如何影响肝硫醇氧化还原的信息很少 信号和控制网络。我们的初步数据支持酒精代谢，蛋白质的观念 乙酰化和CYS氧化还原高度相关。因此，我们提出了一种创新的方法 研究酒精代谢如何影响硫醇氧化还原信号传导和控制。我们目标的核心，硫醇 氧化还原蛋白质组是一种自适应界面，可提供一种感觉，避免和防御氧化剂的手段 和其他有毒物质。因此，该提议的假设是酒精代谢会影响硫醇氧化还原 通过赖氨酸乙酰化的信号传导和控制，导致肝dyshomeostasis并导致ALD。 我们将研究提出的特定目的，以检验我们的假设：具体目的1：表征改变的硫醇 由于酒精代谢而引起的氧化还原信号传导和控制。特定目标2：利用Sirtuin 1过表达 定义乙酰化 - 雷克斯信号传导和控制的机制。特定目标3：整合氧化还原的机制 Cys和乙酰透析以阐明融合特定的氧化还原信号传导。我们将执行这些研究目标 利用尖端的蛋白质组学和生物信息学方法来揭示新的氧化还原传感机制 在肝细胞内。阐明酒精代谢如何改变肝氧化还原信号传导并通过 新颖的翻译后修饰将支持针对性的临床干预措施的发展 在数百万美国人中改善ALD。