Mouse Models for Alcohol Metabolism and Tissue Injury

酒精代谢和组织损伤的小鼠模型

• 批准号: 8603827
• 负责人: VASILIS VASILIOU
• 金额: $ 2.06万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 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 2014-07-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8603827
• 关键词: 4 hydroxynonenal; Abbreviations; Acute; Affect; Alcohol abuse; Alcohol consumption; Alcohol dehydrogenase; Alcohol dependence; Alcohols; Aldehydes; Animal Model; Antioxidants; Biological Process; Breeding; CYP2E1 gene; Capital; Catalytic Domain; Communities; Cytochrome P450; DNA; Development; Disease; Enzyme Gene; Enzymes; Ethanol; Ethanol Metabolism; Felis catus; Free Radicals; Functional disorder; GCLC gene; Genes; Genetic Polymorphism; Glutamate-Cysteine Ligase; Glutathione; Goals; Hepatocyte; Injury; Intention; Investigation; Knock-out; Knockout Mice; Knowledge; Laboratories; Letters; Mammals; Mediating; Messenger RNA; Mitochondria; Modeling; Molecular; Mus; Mutation; Organ; Oxidative Stress; Pathogenesis; Population; Principal Investigator; Proteins; Reactive Nitrogen Species; Reactive Oxygen Species; Reduced Glutathione; Research; Research Personnel; Role; System; Tissues; Toxic effect; Transgenic Animals; Transgenic Mice; Transgenic Organisms; adduct; alcohol effect; alcohol research; aldehyde dehydrogenases; catalase; chronic alcohol ingestion; effective therapy; knockout animal; knockout gene; mouse model; tool

DESCRIPTION (provided by applicant): The goal of this application Is to maintain transgenic knockout animal models that are unique and have high relevance to alcohol research. Alcohol-induced toxicity commonly Involves oxidative stress. Ethanol metabolism by microsomal and mitochondrial systems generates reactive oxygen species and reactive nitrogen species, and is associated with diminished glutathione (GSH) and antioxidant enzymatic activity. In addition, the accumulation of ethanol-derived aldehydes and hydroxyethyl radical 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 will facilitate investigation of the role these enzymes and oxidative stress In diseases associated with ethanol consumption. Therefore, we propose: Specific Aim 1: To maintain the populations of existing mouse models in our laboratory so that they are readily available to researchers. Our current models include: a) the conventlonal7\/c(/77af, Aldhlbl, Aldh2, Cat, Cyp2e1, Adhi and Gclm single knockouts, b) the Cat/Cyp2e1 double knockout, and c) the hepatocyte-specific Gclc^^ knockout and the conditional Gclc '^floxed strain. Specific Aim 2: To generate (and maintain) unique additional mouse knockout models so that they are readily available to researchers. These Include: a) Cyp2e1/Adh1, Cat/Cyp2e1, Cat/Adhi and Cat/Cyp2e1/Adh1 triple knockout, b) Aldhlal/Aldhlbl, Aldh1b1/Aldh2 and the Aldh1a1/Aldh1b1/Aldh2 triple knockout strains, and c) Gclm/Cyp2e1 and Gclm/Aldhlal double knockout strains. Our overarching aim Is to make valuable transgenic animal models available to the larger research community. It is expected that enhanced access to such models will accelerate our understanding of the mechanisms underlying alcohol-Induced disease and the pathophysiological effects of acute and chronic alcohol consumption. Such knowledge would facilitate the development of more effective treatments of alcohol abuse. RELEVANCE: Alcohol-Induced toxicity is associated with oxidative stress resulting from ethanol metabolism that generates reactive oxygen species and Is associated with reduced glutathione (GSH). The goal of this application Is to maintain and expand animal models with genetic defects In alcohol metabolizing enzymes and In GSH synthesizing enzymes that will become available to the research community.

描述（由申请人提供）：本申请的目的是维持独特的转基因敲除动物模型，并且与酒精研究具有很高的相关性。酒精引起的毒性通常涉及氧化应激。微粒体和线粒体系统的乙醇代谢产生活性氧和活性氮种，并且与谷胱甘肽（GSH）（GSH）（GSH）和抗氧化剂酶活性降低有关。另外，乙醇衍生的醛和羟基乙基自由基的积累通过用蛋白质和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在遗传上的可用性将有助于研究这些酶和与乙醇消耗相关的疾病中的作用和氧化应激。因此，我们提出：特定目的1：维持实验室中现有小鼠模型的种群，以便研究人员很容易获得。我们当前的模型包括：a）章程7 \/c（/77af，aldhlbl，aldh2，cat，cyp2e1，adhi和gclm单淘汰量，b）cat/cyp2e1 double敲除，c）肝细胞特异性的gclc ^^ gclc ^^ nockout and gclc' 特定目的2：生成（并维护）独特的其他鼠标敲除模型，以便研究人员很容易获得。其中包括：a）cyp2e1/adh1，cat/cyp2e1，cat/adhi和cat/cyp2e1/adh1三重淘汰，b）aldhlal/aldhlbl，aldh1b1/aldh2，aldh1b1/aldh2以及aldh1a1/aldh1a1/aldh1b1/aldh1b1/aldh1b1/aldh1 triple strains and cipp2 GCLM/Aldhlal双敲除菌株。 我们的总体目的是使较大的研究社区可用的有价值的转基因动物模型。可以预期，加强这种模型的机会将加速我们对酒精诱发疾病的机制以及急性和慢性酒精消耗的病理生理影响。这种知识将促进对酗酒的更有效治疗的发展。相关性：酒精诱导的毒性与乙醇代谢产生的氧化应激有关，乙醇代谢产生活性氧，并且与谷胱甘肽降低有关（GSH）。该应用的目的是在酒精代谢酶和GSH合成酶中维持和扩展具有遗传缺陷的动物模型，这些酶将可用于研究界。