Pharmacogenomic Analysis of Nicotine Dependence

项目描述 吸烟是美国最大的可预防的死亡和疾病原因，约有4600万美国人吸烟。 目前吸烟的成年人（CDC，2007）。 虽然有药物被FDA批准用于治疗尼古丁 一项评估其中两种药物伐尼克兰和安非他酮的临床研究表明，至少80%的 在一年内复发的治疗组参与者（冈萨雷斯，等， 2006年）。 有趣的是， 戒烟已经显示出具有遗传贡献（Xian等人，2003~ Broms等人，2006年~列索夫 例如， 2004年）。 虽然新化合物的开发可能会产生更有前途的药物，但一种新的策略 根据遗传信息定制药物疗法是尼古丁成瘾治疗的下一个前沿（Ho 例如， 2010年）。 然而，尽管有全基因组关联研究表明， 尼古丁成瘾的贡献，没有发表的研究解决的机制， 治疗尼古丁依赖的药物遗传学。 一种蛋白质与两种基因的机制有关 调节和尼古丁反应的转录因子是CREB。本提案中概述的实验旨在 研究CREB和相关基因组机制在潜在治疗应用中的作用， 用于治疗尼古丁成瘾的两种烟碱化合物，并使用 尖端的分子功能和行为技术 到目前为止，我在尼古丁领域的研究 给了我一个坚实的基础，在基础科学的方法，包括生物化学，药理学，和动物 行为 然而，K99期间提出的基因组学和功能成像方面的专门培训 这个奖项的第一阶段将扩大我的知识基础，并增加我的研究的翻译影响。 此外，这个培训和个性化的研究项目将有助于我在求职过程中， 学术终身职位

Project Description 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 the 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.