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.

项目概要 饮酒导致全球约 6% 的死亡，是发病的主要原因 和美国境内的死亡率。这些统计数据表明迫切需要了解 酒精毒性的生化机制和酒精相关性肝病的发病机制 （ALD）。慢性酒精代谢影响许多细胞途径，包括糖酵解、脂质代谢、 TCA 循环以及抗氧化和炎症反应。之间存在已知的生化联系 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）； 然而，关于慢性酒精代谢如何影响肝脏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这样的观点：酒精代谢、蛋白质 乙酰化和Cys氧化还原高度相关。因此，我们提出了一种创新方法 研究酒精代谢如何影响硫醇氧化还原信号和控制。我们目标的核心是硫醇 氧化还原蛋白质组是一种自适应界面，提供了一种感知、避免和防御氧化剂的方法 和其他有毒物质。因此，该提案的假设是酒精代谢影响硫醇氧化还原 通过赖氨酸乙酰化进行信号传导和控制，导致肝脏稳态失调并导致 ALD。 我们将研究所提出的具体目标来检验我们的假设：具体目标 1：表征改变的硫醇 酒精代谢引起的氧化还原信号传导和控制。具体目标 2：利用 Sirtuin 1 过表达 定义乙酰化-氧化还原信号传导和控制的机制。具体目标 3：整合氧化还原机制 Cys 和乙酰基-Lys 阐明 CoAlation 特异性氧化还原信号传导。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揭示新颖的氧化还原传感机制 肝细胞内。阐明酒精代谢如何改变肝脏氧化还原信号和控制 新颖的翻译后修饰将支持有针对性的临床干预措施的开发 改善数百万美国人的 ALD。