Mouse Models for Alcohol Metabolism and Tissue Injury

酒精代谢和组织损伤的小鼠模型

基本信息

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
项目类别：
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

项目摘要

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）：本申请的目标是维持独特且与酒精研究高度相关的转基因敲除动物模型。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，并与谷胱甘肽 (GSH) 和抗氧化酶活性降低有关。此外，乙醇衍生的醛和羟乙基自由基的积累可通过与蛋白质和 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经过基因改造的动物模型的可用性将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。因此，我们建议：具体目标 1：维持我们实验室现有小鼠模型的种群，以便研究人员可以随时使用它们。我们当前的模型包括：a) 传统7\/c(/77af、Aldhlbl、Aldh2、Cat、Cyp2e1、Adhi 和 Gclm 单敲除，b) Cat/Cyp2e1 双敲除，以及 c) 肝细胞特异性 Gclc^^ 敲除和条件 Gclc '^floxed 菌株。具体目标 2：生成（并维护）独特的额外小鼠敲除模型，以便研究人员可以轻松使用它们。这些包括：a) Cyp2e1/Adh1、Cat/Cyp2e1、Cat/Adhi 和 Cat/Cyp2e1/Adh1 三重敲除菌株，b) Aldhlal/Aldhlbl、Aldh1b1/Aldh2 和 Aldh1a1/Aldh1b1/Aldh2 三重敲除菌株，以及 c) Gclm/ Cyp2e1 和 Gclm/Aldhal 双敲除菌株。我们的首要目标是为更大的研究界提供有价值的转基因动物模型。预计增加对此类模型的获取将加速我们对酒精诱发疾病的机制以及急性和慢性饮酒的病理生理学影响的理解。这些知识将有助于开发更有效的酗酒治疗方法。相关性：酒精引起的毒性与乙醇代谢产生的活性氧产生的氧化应激有关，并且与还原型谷胱甘肽 (GSH) 有关。该应用的目标是维持和扩展酒精代谢酶和谷胱甘肽合成酶中具有遗传缺陷的动物模型，这些模型将可供研究界使用。