Alcohol Effects on the Mitochondrial Genetic System

酒精对线粒体遗传系统的影响

• 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
• 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' -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

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.

申请中概述了酗酒造成的健康和经济损失的统计数据。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对线粒体DNA造成了特别严重的损害，这是基于低剂量暴露无法预测的，以前也没有测量过。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！主要是东亚人，缺乏这种酶。我的合作者Shinya Shibutani博士和我在DNA损伤和修复方面拥有相当丰富的专业知识，可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EtOH暴露可能会产生有价值的见解，该项目与mtDNA损伤有关的部分令人兴奋，可能会使该领域更加清晰。“这一评论提供了一个很好的总结，最终产品所提供的我们重新调整重点的研究计划。我们将提供迄今为止最全面的调查，以了解过量酒精暴露引起的mtDNA损伤类型。这项研究旨在检测我们认为被以前的研究忽视的三种重要类型的mtDNA损伤，即脂质过氧化损伤，乙醛加合物和蛋白质-DNA交联。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mtDNA中DNA损伤的谱和丰度不同。