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

描述（由申请人提供）：本申请是根据NIH公告（RFA-OD-09-003）提交的，提案涉及广泛的挑战领域（08）：基因组学和特定的挑战主题08-AA-104：区域中枢神经系统（CNS）基因表达。酒精（乙醇）滥用和依赖是美国的重大医疗和社会问题，并构成重大的公共卫生问题。酒精中毒是一种慢性复发性疾病，复发是治疗工作的一个重大挑战。尽管我们对驱动这种阴险的成瘾循环的神经基质和环境因素的理解取得了重大进展，但几乎没有可用的治疗方法，并且没有一种治疗方法被证明在解决这个问题方面完全令人满意。因此，该领域的一个主要挑战是采用临床前模型，不仅有助于推进我们对持续重度乙醇使用/滥用的病因学因素的了解，而且还确定了新的潜在治疗靶点，这将是下一代治疗方法开发的关键。我们已经开发了一种乙醇依赖和复发饮酒的小鼠模型，该模型非常适合用于旨在确定有助于增强复发脆弱性以及推动乙醇饮酒升级的分子神经生物学事件的研究。本研究的目的是利用这个建立的酒精依赖和复发饮酒的小鼠模型，结合微阵列技术和信息学来分析与酒精依赖相关的过度饮酒相关的基因表达变化。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，以促进识别与慢性乙醇暴露、急性和长期戒断阶段相关的独特的大脑区域和时间依赖性分子事件（mRNA丰度），以及乙醇消费影响这些变化的潜力。因此，这种全面的实验方法将产生非常丰富的数据集，表明基因表达的变化，这是独特的每个这些方面的模型，以及转录改变的途径/功能是共同的跨时间点和大脑区域。反过来，这个非常独特的数据集不仅提供了关于依赖和有害饮酒问题相关机制的新的和有价值的见解，而且还为揭示潜在的新的和新颖的治疗靶点提供了宝贵的资源，这些靶点可能特别有益于为这一重大医学和社会问题（即酒精滥用和酒精中毒）开发更有效的治疗方法。 公共卫生相关性：该项目旨在确定与酒精依赖相关的过度饮酒相关的遗传和分子神经适应性事件，希望揭示潜在的新的和新颖的治疗靶点，以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.