Mouse Models and Metabolomics Tools to Investigate Alcohol Metabolism and Tissue Injury

研究酒精代谢和组织损伤的小鼠模型和代谢组学工具

• 批准号: 10231089
• 负责人: VASILIS VASILIOU
• 金额: $ 51.12万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231089
• 关键词: Abbreviations; Acetaldehyde; Acute; Affect; Alcohol abuse; Alcohol consumption; Alcohol dehydrogenase; Alcohol dependence; Alcohols; Aldehydes; Animal Model; Antioxidants; Biochemical; Biochemical Pathway; Bioinformatics; Biological Process; CYP2E1 gene; Cancer Model; Capital; Catalytic Domain; Cells; Collaborations; Colon Carcinoma; Communities; Consultations; Cytochrome P450; DNA; Detection; Development; Disease; Enzymes; Ethanol; Ethanol Metabolism; Ethanol toxicity; Experimental Designs; Felis catus; GCLC gene; GCLM gene; Genes; Genetic Polymorphism; Glutamate-Cysteine Ligase; Glutathione; Goals; Hepatocyte; Image; In Situ; Intention; Investigation; Italy; Knock-out; Knockout Mice; Knowledge; Letters; Lipids; LoxP-flanked allele; Malignant Neoplasms; Mammals; Maps; Mass Spectrum Analysis; Mediating; Messenger RNA; Metabolic; Methodology; Mitochondria; Modeling; Molecular; Molecular Weight; Mus; Mutagenesis; Mutation; National Institute on Alcohol Abuse and Alcoholism; Nitrogen; Oxidative Stress; Oxygen; Pathogenesis; Play; Population; Predisposition; Process; Proteins; Reactive Nitrogen Species; Reactive Oxygen Species; Research; Research Personnel; Resources; Role; Sampling; System; Techniques; Tissue imaging; Tissues; Toxic effect; Transgenic Animals; Transgenic Mice; Transgenic Organisms; adduct; alcohol abuse therapy; alcohol consequences; alcohol effect; alcohol exposure; aldehyde dehydrogenases; catalase; cell injury; chronic alcohol ingestion; conditional knockout; effective therapy; gene product; insight; knockout gene; metabolomics; metabolomics resource; mouse model; mutant; nuclear factor-erythroid 2; small molecule; symposium; tissue injury; tool

ABSTRACT The deleterious effects of alcohol are primarily mediated by its metabolic by-products. Ethanol metabolism by microsomal and mitochondrial systems generates reactive oxygen and nitrogen species, and is associated with diminished glutathione and antioxidant enzymatic activity, all of which promote oxidative stress. In addition, the accumulation of ethanol-derived aldehydes and hydroxyethyl radicals serves to modify critical biological functions by forming adducts with proteins and DNA. The availability of animal models in which ethanol metabolism or antioxidant mechanisms are genetically modified facilitates investigation of the role these enzymes and oxidative stress play in diseases associated with ethanol consumption. The goals of this application are to: A) maintain and develop unique transgenic knockouts that can be made available to the larger research community for the investigation of the pathogenesis of alcohol abuse and the mechanisms underlying the deleterious effects of alcohol, and B) offer metabolomics and tissue imaging mass spectrometry (IMS) expertise to facilitate investigation of the biochemical consequences of alcohol exposure and pathogenesis. Our overarching aim is to provide valuable transgenic animal models and metabolomics resources to the larger research community that will greatly enhance our understanding of the mechanisms underlying alcohol-induced disease and the pathophysiological effects of acute and chronic alcohol consumption. It is anticipated that our metabolomic platforms will offer state-of-the-art techniques to dissect the molecular mechanisms of alcohol-induced tissue injury. Such knowledge will facilitate the development of more effective treatments of alcohol abuse.

摘要 酒精的有害作用主要是由其代谢副产物介导的。微粒体乙醇代谢 线粒体系统产生活性氧和氮，并与谷胱甘肽减少有关 和抗氧化酶活性，所有这些都促进氧化应激。此外，乙醇衍生物的积累 醛和羟乙基自由基通过与蛋白质和DNA形成加合物来改变关键的生物功能。 乙醇代谢或抗氧化机制被基因修饰的动物模型的可用性有助于 研究这些酶和氧化应激在与乙醇消耗相关的疾病中的作用。的 本申请的目的是：A）维持和开发独特的转基因敲除， 更大的研究社区，调查酒精滥用的发病机制和潜在的机制， 酒精的有害作用，和B）提供代谢组学和组织成像质谱（IMS）专业知识，以促进 调查酒精暴露的生化后果和发病机制。我们的首要目标是提供 有价值的转基因动物模型和代谢组学资源，以更大的研究社区，将大大提高 我们对酒精引起的疾病的机制以及急性和慢性酒精中毒的病理生理学影响的理解， 长期饮酒预计我们的代谢组学平台将提供最先进的技术来解剖 酒精诱导组织损伤的分子机制。这些知识将有助于制定更有效的 酒精滥用的治疗。