Treatment and Gene/Protein Analysis of Ethanol Relapse

乙醇复发的治疗和基因/蛋白质分析

• 批准号: 6556196
• 负责人: HOWARD C. BECKER
• 金额: $ 36.5万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6556196
• 关键词: alcoholic beverage consumption; alcoholism /alcohol abuse; alcoholism /alcohol abuse chemotherapy; antisense nucleic acid; behavioral /social science research tag; behavioral genetics; disease /disorder model; drug abuse prevention; drug withdrawal; ethanol; gene expression; genetic susceptibility; genome; immunocytochemistry; laboratory mouse; microarray technology; neurobiology; neuropsychology; nonhuman therapy evaluation; polymerase chain reaction; proteomics; relapse /recurrence; western blottings

DESCRIPTION (provided by applicant): Alcohol abuse continues to be a substantial medical and social problem in the United States. A complex interplay among numerous biological and environmental factors influences ETOH drinking behavior. Chronic excessive consumption of ETOH can lead to the development of dependence, and repeated experience with associated withdrawal episodes may constitute a powerful motivational force that perpetuates continued ETOH use/abuse, as well as contributing to relapse (i.e., the re-initiation of drinking after periods of abstinence). Given the high rate of recidivism in alcoholism, it is clear that relapse represents a major problem for most alcoholics, and relapse continues to represent a major challenge to treatment efforts. Currently, there is no therapeutic intervention (including pharmacotherapy) that is fully satisfactory in preventing relapse and sustaining abstinence. Thus, the development and use of preclinical models of ETOH relapse that closely approximate the clinical situation is essential for advancing investigations aimed at elucidating neural substrates and environmental circumstances that precipitate and/or mediate relapse, as well as facilitating the evaluation of more effective treatment strategies. The focus and overall objective of this proposal is to utilize a mouse model of repeated ETOH withdrawals and relapse to evaluate the efficacy of pharmacotherapies for relapse prevention, as well as identify molecular neurobiological events related to increased relapse susceptibility. Conceivably, changes in gene and protein expression that endure well beyond the presence of ETOH in the brain may represent key molecular adaptive events that are critical in mediating fundamental changes in brain function that define relapse susceptibility. Thus, it follows that identification of long-term changes in gene expression following repeated cycles of chronic ETOH exposure and withdrawal would provide valuable insight about potentially novel targets for new treatment approaches that are especially relevant to battling relapse. To date, there is very little information available about changes in gene expression that may relate to ETOH relapse. Therefore, a unique and novel feature of this proposal is to combine a robust behavioral model of ETOH relapse with sophisticated molecular techniques that involve applying gene arrays for identification of a 'relapse gene profile', followed by immunoblotting to validate the relevance of candidate changes. Further, identifying common molecular targets of pharmacotherapies for relapse prevention has the potential to lead to the development of new treatment strategies that are more effective than current ones in preventing relapse and sustaining abstinence. Thus, the aims and objectives of this proposal reflect an overarching experimental strategy that embodies a behavior-gene-behavior approach. The overall goal of this proposal is to utilize functional genomics/proteomics in a new model of ETOH relapse to evaluate, on a molecular level, the efficacy of various pharmacotherapies, as well as to identify new and novel targets for therapeutic intervention.

描述（由申请人提供）： 在美国，酗酒仍然是一个实质性的医学和社会问题。众多生物学和环境因素之间的复杂相互作用会影响ETOH饮酒行为。长期过度食用ETOH可以导致依赖性的发展，并且与相关撤回发作的反复经验可能构成一种强大的动机力量，使持续的EtOH使用/滥用持续存在，并有助于复发（即，饮酒后的饮酒后，戒酒后的饮酒后重新开始）。鉴于酒精中毒的累犯率很高，很明显，复发代表了大多数酗酒者的主要问题，而复发继续代表了治疗工作的主要挑战。当前，没有治疗性干预（包括药物疗法）在防止复发和持续禁欲方面完全令人满意。因此，与临床状况接近临床状况的ETOH复发模型的开发和使用对于旨在阐明旨在阐明神经底物和环境环境的研究至关重要，这些调查会导致和/或介导复发，并促进评估更有效的治疗策略。该提案的重点和整体目标是利用重复ETOH戒断的小鼠模型并复发来评估药物疗法预防复发的疗效，并确定与复发易感性增加有关的分子神经生物学事件。可以想象，忍受大脑中ETOH的存在的基因和蛋白质表达的变化可能代表关键的分子自适应事件，这些事件对于介导脑功能的基本变化至关重要，从而定义了复发易感性。因此，随之而来的是，在慢性ETOH暴露和戒断的重复循环后，对基因表达的长期变化的鉴定将为可能与与复发作斗争特别相关的新治疗方法的潜在新靶标提供宝贵的见解。迄今为止，几乎没有关于基因表达变化的信息可能与EtOH复发有关。因此，该建议的独特而新颖的特征是将ETOH复发的鲁棒行为模型与复杂的分子技术结合起来，该模型涉及应用基因阵列以鉴定“复发基因谱”，然后进行免疫印迹以验证候选者变化的相关性。此外，确定预防复发的药物疗法的共同分子靶标有可能导致发展新的治疗策略，这些策略比目前的治疗策略在预防复发和维持戒酒方面更有效。因此，该提案的目的和目标反映了一种总体实验策略，该策略体现了行为与行为的方法。该建议的总体目标是在新的ETOH复发模型中利用功能基因组/蛋白质组学，以在分子水平上评估各种药物疗法的功效，并确定治疗干预的新目标。