Pharmacogenomic Analysis of Nicotine Dependence

尼古丁依赖性的药物基因组学分析

• 批准号: 8787883
• 负责人: Jill R. Turner
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8787883
• 关键词: Address; Adult; Affective; Animal Behavior; Anxiety; Award; Basic Science; Behavior; Behavioral; Behavioral Paradigm; Binding; Biochemistry; Bioinformatics; Biological; Bupropion; CREB1 gene; Cause of Death; Centers for Disease Control and Prevention (U.S.); ChIP-seq; Chantix; Chronic; Clinical; Clinical Research; Cognitive; Collaborations; Data; Development; Disease; Dyes; FDA approved; Foundations; Functional Imaging; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Transcription; Genome; Genomics; Hippocampus (Brain); Human; Image; Impairment; Individual; Mediating; Modeling; Molecular; Mus; Mutant Strains Mice; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Occupations; Participant; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Pharmacology; Pharmacotherapy; Phase; Population; Positioning Attribute; Proteins; Publishing; Recording of previous events; Relapse; Research; Research Personnel; Research Project Grants; Role; Saline; Single Nucleotide Polymorphism; Smoking; Solid; Techniques; Testing; Therapeutic; Training; United States; United States National Institutes of Health; Validation; Withdrawal; clinically relevant; field study; frontier; functional genomics; genome wide association study; human NRG3 protein; improved; knowledge base; novel; object recognition; public health relevance; research study; response; smoking cessation; smoking relapse; success; transcription factor; varenicline; voltage

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.

项目说明 吸烟是美国最大的可预防的死亡和疾病原因，美国约有4600万人。 目前吸烟的成年人(CDC，2007)。尽管有FDA批准的治疗尼古丁的药物 一项评估其中两种药物伐伦克林和安非他酮的临床研究显示，至少80%的人 在治疗组中，参与者在一年内复发(Gonzales等人，2006年)。有趣的是，失败了 戒烟已被证明具有遗传贡献(Xian等人，2003~Broms等人，2006~Lessov 等人，2004年)。尽管开发新化合物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治疗是尼古丁成瘾治疗的下一个前沿 等人，2010年)。然而，尽管有全基因组关联研究表明， 在尼古丁成瘾中的作用，目前还没有发表的关于尼古丁成瘾的机制的研究 治疗尼古丁依赖的药物遗传学。一种与这两个基因的机制相关的蛋白质 调节和尼古丁反应的转录因子是CREB。这项提案中概述的实验旨在 探讨CREB及其相关基因组机制在糖尿病治疗中的潜在应用 两种治疗尼古丁成瘾的尼古丁化合物，并阐明了可能的作用机制 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 使我在基础科学方法方面有了坚实的基础，包括生物化学、药理学和动物 行为。然而，在K99期间，基因组学和功能成像方面提出的专门培训 这个奖项的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，这个培训和个性化研究项目将很好地帮助我在找工作的过程中 学术终身教职-跟踪职位。