Alcohol Effects on the Mitochondrial Genetic System

酒精对线粒体遗传系统的影响

• 批准号: 7522446
• 负责人: DANIEL F. BOGENHAGEN
• 金额: $ 39万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7522446
• 关键词: 8-Oxo-2' -Deoxyguanosine; Acetaldehyde; Acute; Alcohol abuse; Alcohol consumption; Alcohols; Animals; Asians; Binding Proteins; Budgets; Cells; Chemicals; Chronic; DNA; DNA Damage; DNA Repair; DNA-Directed DNA Polymerase; DNA-protein crosslink; Diet; Dose; Enzymes; Equilibrium; Ethanol Metabolism; Ethanol toxicity; Faculty; Failure; Funding; Genetic; Genetic Models; Genotype; Goals; Human; Human Resources; Incidence; Individual; Intoxication; Kinetics; Knock-out; Knockout Mice; Laboratories; Lead; Learning; Lesion; Lipid Peroxidation; Liver; Marketing; Measures; Mitochondria; Mitochondrial DNA; Modeling; Mouse Strains; Mus; Nature; New Jersey; Nuclear; Pathway interactions; Positioning Attribute; Postdoctoral Fellow; Proteins; Publications; Published Comment; Publishing; Reactive Oxygen Species; Recommendation; Recovery; Refractory; Reporter; Research; Source; Surveys; System; Testing; Tissue Sample; Unemployment; Universities; Visit; Work; acetaldehyde dehydrogenase; adduct; alcohol effect; alcohol exposure; base; binge drinking; cell injury; crosslink; design; drinking; economic cost; economic impact; enzyme deficiency; experience; human tissue; insight; interest; meetings; oxidative damage; programs; repaired; 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.

申请书中概述了与酒精滥用有关的健康和经济成本的统计数据。我们认为，乙醛脱氢酶2活性降低的人急性中毒和饮酒的后果对线粒体DNA造成特别严重的损伤，这是基于低剂量暴露无法预测的，也是以前没有测量到的。由于这是一项侵入性研究，我们不能使用人类组织进行这项研究，但将使用野生型和AldhZ‘-小鼠。这种击倒老鼠的品系提供了一种模式！对于人类，主要是东亚人，这种酶缺乏。我的合作者Shinya Shibutani博士和我在DNA损伤和修复方面带来了相当多的专业知识，解决了酒精引起的线粒体损伤这一具有医学和社会意义的问题。对最初申请的审查指出，“急性和慢性乙醇暴露的使用可能会产生有价值的见解，项目中与线粒体DNA损伤有关的部分令人兴奋，可能会给这一领域带来澄清。”这篇评论很好地总结了我们重新聚焦的研究计划所提供的最终产品。我们将提供迄今为止最全面的调查，调查过度饮酒对线粒体DNA的损伤类型。这项研究旨在检测我们认为被以往研究忽视的三种重要的线粒体DNA损伤类型，即脂质过氧化损伤、乙醛加合物和蛋白质-DNA交联链。作为我们方法的一部分，我们将评估相同组织样本中的核DNA损伤，以验证我们的假设，即DNA损伤的光谱和丰度在核DNA和线粒体DNA中将不同。