Pharmacogenomic Analysis of Nicotine Dependence

描述(由申请人提供)：吸烟是美国最大的可预防的死亡和疾病原因，目前约有4600万美国成年人吸烟(CDC，2007)。尽管FDA批准了治疗尼古丁成瘾的药物，但一项评估其中两种药物--varenicline和安非他酮的临床研究显示，至少80%的治疗组参与者在一年内复发(Gonzales，et al.，2006)。有趣的是，戒烟失败也有遗传贡献(Xian等人，2003~Broms等人，2006~Lessov等人，2004)。尽管开发新化合物可能会产生更有前景的药物，但根据遗传信息定制药物治疗的新策略是尼古丁成瘾治疗的下一个前沿(Ho等人，2010年)。然而，尽管有全基因组的关联研究表明基因在尼古丁成瘾中的作用，但还没有发表过关于药物遗传学治疗尼古丁依赖的机制的研究。与基因调控和尼古丁反应机制相关的一种蛋白质是转录因子CREB。本提案中概述的实验旨在研究CREB及其相关的基因组机制在两种尼古丁化合物治疗尼古丁成瘾的潜在治疗应用中的作用，并利用尖端的分子、功能和行为技术阐明可能的作用机制。到目前为止，我在尼古丁领域的研究给了我在基础科学方法方面的坚实基础，包括生物化学、药理学和动物行为。然而，在该奖项的K99阶段建议的基因组学和功能成像方面的专门培训将拓宽我的知识基础，并增加我的研究的翻译影响。此外，这个培训和个性化研究项目将很好地帮助我寻找学术终身教职的职位。

DESCRIPTION (provided by applicant): Smoking is the largest preventable cause of death and disease in the United States, with about 46 million U.S. Adults currently smoking (CDC, 2007). Though there are medications approved by the FDA to treat nicotine addiction, a clinical study evaluating two of these drugs, varenicline and bupropion, showed that at least 80% of the treatment group participants relapsed within one year (Gonzales, et al., 2006). Interestingly, failed smoking cessation has been shown to have genetic contributions (Xian et al., 2003~ Broms et al., 2006~ Lessov et al., 2004). Though development of novel compounds may yield more promising drugs, a new strategy tailoring pharmacotherapies to genetic information is the next frontier in the treatment of nicotine addiction (Ho et al., 2010). However, though there are genome-wide association studies demonstrating a genetic contribution in nicotine addiction, there are no published studies addressing th mechanism of pharmacogenetics in treating nicotine dependence. One protein associated with mechanisms of both gene regulation and nicotine response is the transcription factor CREB. Experiments outlined in this proposal aim to investigate the role of CREB and associated genomic mechanisms in the potential therapeutic application of two nicotinic compounds for treatment of nicotine addiction, and elucidate possible mechanisms of action using cutting-edge molecular, functional, and behavioral techniques. My research so far in the nicotinic field has given me a solid foundation in basic science approaches, including biochemistry, pharmacology, and animal behavior. However, the specialized training proposed in genomics and functional imaging during the K99 phase of this award will broaden my knowledge base and increase the translational impact of my research. Furthermore, this training and individualized research project will serve me well during job searches for an academic tenure-track position.