Using DNA Methylation to Determine Recent Alcohol Consumption Patterns

描述（由申请人提供）：酗酒是一种普遍现象，是一种重大的社会/经济挑战。虽然长期少量饮酒并不总是有害的，但大量饮酒（每天50到20杯）通常是有害的，并经常导致酒精中毒——最常见的形式是酒精滥用（AA）和酒精依赖（AD）。AA/AD影响了25%的美国人口，每年造成近2000亿美元的经济损失和无法估量的人类痛苦。如果及早发现酒精滥用，这些不良后果是可以避免的；然而，目前慢性酒精使用的筛查方法仅在检测前几小时内捕获酒精使用情况，或依赖于不敏感的非特异性蛋白质测定。一种能够更可靠地识别慢性酒精滥用和监测戒酒情况的下一代方法将引起包括医疗、政府、安全和运输机构在内的许多团体的极大兴趣。开发、验证和商业化这种下一代技术是Behavioral Diagnostic公司的总体目标。在第一阶段的可行性研究中，我们将以我们在物质使用表观遗传学方面的丰富经验为基础，寻求实现两个目标。首先，我们将明确证明与酒精使用相关的甲基化总体模式是可靠的。其次，我们将确定在没有立即饮酒的情况下DNA甲基化的稳定性。在这个第一阶段的项目中，我们建议首先通过比较戒酒对照者与急性解毒重度饮酒者的甲基化谱来验证先前酒精相关DNA甲基化变化的全基因组分析结果。然后，我们将对这些饮酒者进行为期30天的住院治疗，并在30天的住院治疗后检查甲基化程度差异最大的甲基化残留物，以确定哪些是稳定的（特征标记），哪些是开始恢复到群体平均水平的过程（状态标记和可能的治疗相关戒断指标）。如果成功，该项目将是该领域的重大进步，并将为我们二期全面诊断工具的开发提供原理证明，该工具可用于检测和定量慢性酒精使用，并监测出院后患者的戒断情况。这一极具创新性的建议意义重大，因为为这些疾病开发易于使用、相对万无一失的诊断测试可能在医疗、民事和法医应用中得到广泛接受。该公司做好了进行研究的充分准备，原因有几个。首先，Philibert博士是该技术的共同发明者，是一名委员会认证的精神科医生，在拟议研究的各个方面都有丰富的经验，并有直接监督本研究任何潜在的第二阶段的能力。其次，Osborn博士，首席执行官，在生物产业有30年的经验，与生物医学和生物风险社区有着良好的联系。第四，我们得到了一个由伦理学家和药物使用专家组成的团队的进一步帮助。第四，公司对该技术和其他相关技术拥有知识产权。

DESCRIPTION (provided by applicant): Heavy alcohol use is common and presents a major social/economic challenge. Although chronic use of small amounts of alcohol is not always harmful, heavier use (>2 drinks/day) is generally harmful and frequently leads to alcoholism-the most common forms being alcohol abuse (AA) and alcohol dependence (AD). AA/AD affect ~25% of the U.S. population and cause nearly $200 billion/yr of economic damage and untold human misery. These adverse outcomes are potentially avoidable if the alcohol abuse is spotted early; however, current screening methods for chronic alcohol use capture alcohol usage only in the hours prior to testing or rely on insensitive, non-specific protein assays. A next-generation method that could more reliably identify chronic alcohol abuse and monitor abstinence would be of great interest to a large number of groups, including medical, governmental, security and transportation agencies. Developing, validating, and commercializing such a next-generation technology is Behavioral Diagnostic's overall goal. In this Phase I feasibility study, we will build upon our extensive experience in substance use epigenetics and will seek to achieve two goals. First, we will unequivocally demonstrate that the overall patterns of methylation associated with alcohol use are reliable. Second, we will determine the stability of DNA methylation in the absence of immediate alcohol use. In this Phase I project, we propose to do this by first validating the results from a prior genome-wide analysis of alcohol associated DNA methylation changes by comparing the methylation profiles of abstinent controls with that of heavy drinkers admitted for acute detoxication. We will then follow these drinkers through a 30 day inpatient treatment stay and check methylation at the most significantly differentially methylated residues after 30 days of inpatient assured abstinence to determine which are stable (trait marker) and which start the process of reverting to the population mean (state marker and possible indicator of treatment associated abstinence). If successful, this project will be a significant advancement for the field and will serve as proof of principle for our Phase II development of a full-scale diagnostic tool for both the detection and quantitation of chronic alcohol use and monitor abstinence in patients after discharge. This highly innovative proposal is significant because the development of easy to use, relatively foolproof diagnostic tests for these disorders could find widespread acceptance in medical, civil and forensic applications. The company is well prepared to conduct the studies for several reasons. First, Dr. Philibert, is a co-inventor of the technology, is a board certified psychiatrist with extensive experience in all aspects of the proposed studies , and has direct capability of overseeing any potential Phase II of this study. Second, Dr. Osborn, the CEO, has thirty years of experience in bio-industry and is well connected to the biomedical and bioventure communities. Fourth, we are further aided by a team of ethicists and substance use specialists. Fourth, the company has secured intellectual properties rights with respect to this and other related technologies.