Gene Expression Profiling in a Mouse Model of Ethanol Dependence and Drinking

描述(由申请人提供)：本申请是针对美国国立卫生研究院的公告(RFA-OD-09-003)而提交的，该提案涉及广泛的挑战领域(08)：基因组学，以及特定的挑战主题08-AA-104：区域中枢神经系统(CNS)基因表达。酒精滥用和依赖在美国是严重的医疗和社会问题，构成了一个重大的公共卫生问题。酒精中毒是一种慢性复发性疾病，复发是治疗努力的主要挑战。尽管我们对神经底物和环境因素的了解有了很大的进步，但几乎没有可用的治疗方法，也没有一种方法被证明在解决这个问题上完全令人满意。因此，该领域的一个主要挑战是采用临床前模型，这些模型不仅有助于提高我们对长期大量使用/滥用乙醇的病因的了解，而且还可以确定新的潜在治疗靶点，这些靶点将是下一代治疗方法的关键。我们已经开发了一种酒精依赖和复发饮酒的小鼠模型，该模型非常适合于旨在确定导致复发易感性增加以及推动酒精饮酒升级的分子神经生物学事件的研究。这项研究计划旨在利用建立的酒精依赖和反复饮酒的小鼠模型，结合基因芯片技术和信息学来描述与酒精依赖相关的过度饮酒相关基因表达的变化。该提案的一个新颖和创新的特点是，它需要应用复杂的分析工具来促进识别与慢性酒精暴露、急性和长期戒断阶段有关的独特的大脑区域性和时间相关的分子事件(mRNA丰度)，以及酒精消费影响这些变化的可能性。因此，这种全面的实验方法将产生一个非常丰富的数据集，表明模型中这些方面独一无二的基因表达变化，以及跨时间点和大脑区域常见的途径/功能的转录变化。这一高度独特的数据集不仅将为与依赖和有害饮酒问题相关的机制提供新的和有价值的见解，而且还将为该领域提供宝贵的资源，揭示潜在的新的治疗目标，这些目标可能特别有助于努力开发更有效的治疗这一重大医学和社会问题的方法，即酗酒和酗酒。 公共卫生相关性：该项目旨在确定与过度饮酒和酒精依赖相关的遗传和分子神经适应事件，以期揭示潜在的新的治疗目标，开发新的酒精中毒治疗方法。

DESCRIPTION (provided by applicant): This application is submitted in response to the NIH Announcement (RFA-OD-09-003) and the proposal addresses the broad Challenge Area (08): Genomics, and the specific Challenge Topic, 08-AA-104: Regional Central Nervous System (CNS) Gene Expression. Alcohol (ethanol) abuse and dependence are substantial medical and social problems in the U.S. and constitute a significant public health concern. Alcoholism is a chronic relapsing disease, and relapse represents a major challenge to treatment efforts. Despite significant advancements in our understanding about neural substrates and environmental factors that drive this insidious cycle of addiction, few treatments are available and none have proven to be fully satisfactory in tackling this problem. Thus, a major challenge to the field is to employ preclinical models that not only facilitate advancing our knowledge about etiological factors involved in perpetuating heavy ethanol use/abuse, but also identifying new potential therapeutic targets that will be key in the development of the next generation of treatments. We have developed a mouse model of ethanol dependence and relapse drinking that is ideally suited for studies aimed at identifying molecular neurobiological events that contribute to enhanced relapse vulnerability as well as driving escalation of ethanol drinking. This research proposal is aimed at utilizing this established mouse model of ethanol dependence and relapse drinking in combination with microarray technology and informatics to profile changes in gene expression related to excessive drinking associated with ethanol dependence. A novel and innovative feature of the proposal is that it entails applying sophisticated analytical tools to facilitate identification of unique brain regional and time-dependent molecular events (mRNA abundance) related to chronic ethanol exposure, acute and protracted phases of withdrawal, and the potential for ethanol consumption to impact these changes. Thus, this comprehensive experimental approach will generate a very rich data set indicating changes in gene expression that are unique to each of these aspects of the model as well as transcriptional alterations in pathways/functions that are common across time points and brain regions. This highly unique data set will, in turn, not only provide new and valuable insights about mechanisms relevant to the problem of dependence and harmful drinking, but also provide a valuable resource to the field in revealing potential new and novel therapeutic targets that may be especially informative for efforts to develop more effective treatments for this major medical and social problem, namely alcohol abuse and alcoholism. PUBLIC HEALTH RELEVANCE: This project aims to identify genetic and molecular neuroadaptive events related to excessive drinking associated, with alcohol dependence with the hope of revealing potential new and novel therapeutic targets for development of new treatments for alcoholism.