Mouse Models for Alcohol Metabolism and Tissue Injury

描述（由申请人提供）：本申请的目的是维持与酒精研究高度相关的独特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）减少和抗氧化酶活性有关。此外，乙醇衍生的醛和羟乙基自由基的积累通过与蛋白质和DNA形成加合物来修饰关键的生物功能。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，我们提出：具体目标1：维持我们实验室中现有小鼠模型的种群，以便研究人员随时可用。我们目前的模型包括：a)常规的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。特定目标2：生成（并维护）独特的额外小鼠敲除模型，以便于研究人员随时可用。这些包括：a) Cyp2e1/Adh1, Cat/Cyp2e1， Cat/Adhi和Cat/Cyp2e1/Adh1三敲除株，b) Aldhlal/Aldhlbl， Aldh1b1/Aldh2和Aldh1a1/Aldh1b1/Aldh2三敲除株，以及c) Gclm/Cyp2e1和Gclm/Aldhlal双敲除株。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，增加对这些模型的访问将加速我们对酒精诱发疾病的机制和急性和慢性酒精消费的病理生理效应的理解。这些知识将有助于制定更有效的酗酒治疗方法。相关性：酒精诱导的毒性与乙醇代谢产生活性氧引起的氧化应激有关，并与还原性谷胱甘肽（GSH）有关。本应用程序的目标是维持和扩展具有酒精代谢酶和谷胱甘肽合成酶遗传缺陷的动物模型，这些模型将可用于研究界。

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.