Alcohol Effects on the Mitochondrial Genetic System

酒精对线粒体遗传系统的影响

基本信息

批准号：
7862627
负责人：
DANIEL F. BOGENHAGEN
金额：
$ 39.25万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7862627
关键词：
8-Oxo-2&apos -Deoxyguanosine Acetaldehyde Active Sites Acute Alcohol abuse Alcohol consumption Alcohols Alkylation Asians Base Excision Repairs Binding Borohydrides Cells Chemicals Chronic DNA DNA Damage DNA Repair DNA-protein crosslink Disease Dose E coli AlkB protein Enzymes Ethanol Ethanol Metabolism Ethanol toxicity Genes Genetic Growth Hepatic Hepatocyte Homologous Protein Human Individual Intoxication Knockout Mice Lead Ligase Lipid Peroxidation Liver Lyase Measures Methods Mitochondria Mitochondrial DNA Mitochondrial Proteins Modeling Mouse Strains Mus Nature Navajo Nuclear Oxidative Stress Proteins Proteome Proteomics Published Comment Reaction Reactive Oxygen Species Recovery Relative (related person)Research Schiff Bases Site Surveys System Testing Tissue Sample Yeasts acetaldehyde dehydrogenase adduct alcohol effect alcohol exposure base cell injury crosslink design economic cost enzyme deficiency high risk human tissue in vivo insight novel repaired sodium borohydride statistics

项目摘要

Statistics on the health-related and economic costs of alcohol abuse were summarized in the application. We consider that the consequences of acute intoxication and of alcohol consumption by individuals with reduced acetaldehyde dehydrogenase 2 activity create especially severe damage to mitochondrial DNA that is not predictable based on low-dose exposures and has not been measured previously. Since this is an invasive study, we cannot use human tissues for this research, but will use wild-type and aldhZ'- mice. This knockout mouse strain provides a mode! for humans, mainly East Asians, with this enzyme deficiency. My collaborator, Dr. Shinya Shibutani, and I bring a considerable expertise in DNA damage and repair to the medically and socially important problem of alcohol-induced mitochondrial damage. The review of the original application noted that "the use of both acute and chronic EtOH exposure will likely yield valuable insights and the portions of the project relating to mtDNA damage (are) exciting and likely to bring clarity to the field." This comment provides an excellent summary of the end-product offered by our refocused research plan. We will provide the most comprehensive survey to date of the types of damage to mtDNA that are induced by excessive alcohol exposure. The study is designed to detect three important types of mtDNA damage that we consider have been overlooked by previous studies, namely lipid peroxidation damage, acetaldehyde adducts and protein-DNA cross-links. As part of our approach we will assess damage in nuclear DNA in the same tissue samples to test our hypothesis that the spectrum and abundance of DNA damage will differ in nuclear and mtDNA.

申请中总结了酗酒造成的健康相关和经济成本的统计数据。我们认为，乙醛脱氢酶 2 活性降低的个体急性中毒和饮酒的后果会对线粒体 DNA 造成特别严重的损害，这种损害是基于低剂量暴露无法预测的，并且之前也没有测量过。由于这是一项侵入性研究，我们不能使用人体组织进行这项研究，但将使用野生型和 aldhZ'- 小鼠。这种基因敲除小鼠品系提供了一种模式！对于患有这种酶缺乏症的人类，主要是东亚人。我和我的合作者 Shinya Shibutani 博士在 DNA 损伤和修复方面拥有丰富的专业知识，以解决酒精引起的线粒体损伤这一医学和社会重要问题。对原始申请的审查指出，“使用急性和慢性乙醇暴露可能会产生有价值的见解，并且该项目中与 mtDNA 损伤相关的部分令人兴奋，并且可能会为该领域带来清晰度。”此评论对我们重新调整的研究计划所提供的最终产品进行了精彩的总结。我们将提供迄今为止最全面的调查，了解过量饮酒引起的线粒体 DNA 损伤类型。这项研究旨在检测三种重要的线粒体DNA损伤类型，即脂质过氧化损伤、乙醛加合物和蛋白质-DNA交联，我们认为这三种损伤类型被之前的研究所忽视。作为我们方法的一部分，我们将评估相同组织样本中核 DNA 的损伤，以检验我们的假设，即核 DNA 和线粒体 DNA 中 DNA 损伤的范围和丰度会有所不同。