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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的酒精的有害作用主要是由其代谢副产品介导的。微粒体的乙醇代谢线粒体系统产生活性氧和氮种，并且与谷胱甘肽降低有关和抗氧化剂酶活性，所有酶活性都会促进氧化应激。另外，乙醇衍生的积累醛和羟基乙基自由基通过用蛋白质和DNA形成加合物来改变关键的生物学功能。乙醇代谢或抗氧化剂机制的可用性是基因修饰的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。这该应用程序的目标是：a）维护和开发独特的转基因淘汰赛，可以提供给更大的研究社区调查酒精滥用的发病机理和依据的机制酒精的有害影响，b）提供代谢组学和组织成像质谱（IMS）专业知识以促进研究酒精暴露和发病机理的生化后果。我们的总体目的是提供有价值的转基因动物模型和代谢组学资源向更大的研究社区大大增强我们对酒精引起的疾病的基础机制以及急性和长期饮酒。预计我们的代谢组平台将提供最先进的技术来剖析酒精诱导的组织损伤的分子机制。这种知识将促进更有效的发展酗酒的治疗。