The Collaborative Genetic Study of Nicotine Dependence

尼古丁依赖性的合作遗传学研究

• 批准号: 7874638
• 负责人: Laura J. Bierut
• 金额: $ 161.1万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-28 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7874638
• 关键词: Collaborative; Genetic; Study; Nicotine; Dependence

DESCRIPTION (provided by applicant): This application is for a 5-year renewal of the Collaborative Genetic Study of Nicotine Dependence. Through a genome wide association and candidate gene study, we successfully identified genes contributing to the development of nicotine dependence, such as the alpha5 nicotinic cholinergic receptor subunit, CHRNA5. The goals of this program are the further identification of genes, environmental features, and biological mechanisms that contribute to the onset and persistence of smoking and nicotine dependence. Project 1 builds upon the foundation laid in the past funding period. This project will use phenotypic refinement and sophisticated genetic modeling to analyze existing data, including the nicotine metabolism endophenotype. The goal of this project is to understand how genes affect the susceptibility to develop nicotine dependence and correlated characteristics. Project 2 will use a combination of genetic and functional approaches to further identify specific risk alleles. We will genotype the most significant SNPs from our previous study in an independent case control series. Genes that show evidence of replication will undergo fine mapping and those with the most compelling evidence of association will be examined in vivo and in vitro to determine functional consequences of the risk alleles. This will shed considerable light on the biological mechanisms underlying nicotine dependence. Project 3 adds a translational component to the program by incorporating mouse genetic models of Chrna5. This will identify and characterize reinforcing and aversive properties of nicotine exposure and basic neurobiological mechanisms through which Chrna5/alpha5 contributes to nicotine addiction. Project 4 examines questions central to understanding smoking cessation and relapse. The follow-up of nicotine dependent cases recruited during the past funding period will be the first longitudinal study of addicted smokers from a community based sample. We will test candidate genes for smoking cessation and relapse; test gene interactions; and test association between candidate genes and endophenotypes involved with cessation and relapse. Our synergistic program project uses a powerful trans-disciplinary approach to suggest novel strategies for reducing tobacco consumption and decreasing the morbidity and mortality that follow.

描述（由申请人提供）：本申请旨在将尼古丁依赖性合作遗传研究延期 5 年。通过全基因组关联和候选基因研究，我们成功鉴定了有助于尼古丁依赖发展的基因，例如 α5 烟碱胆碱能受体亚基 CHRNA5。该项目的目标是进一步鉴定导致吸烟和尼古丁依赖的发生和持续的基因、环境特征和生物机制。 项目 1 建立在过去资助期奠定的基础上。该项目将使用表型细化和复杂的遗传模型来分析现有数据，包括尼古丁代谢内表型。该项目的目标是了解基因如何影响尼古丁依赖的易感性和相关特征。 项目 2 将结合使用遗传和功能方法来进一步识别特定的风险等位基因。我们将对之前独立病例对照系列研究中最重要的 SNP 进行基因分型。显示复制证据的基因将进行精细定位，而那些具有最令人信服的关联证据的基因将在体内和体外进行检查，以确定风险等位基因的功能后果。这将为尼古丁依赖的生物学机制提供相当多的线索。 项目 3 通过合并 Chrna5 的小鼠遗传模型，在程序中添加了翻译组件。这将识别和表征尼古丁暴露的增强和厌恶特性以及 Chrna5/alpha5 导致尼古丁成瘾的基本神经生物学机制。 项目 4 研究了理解戒烟和复吸的核心问题。对过去资助期间招募的尼古丁依赖病例的随访将是第一个针对社区样本中的成瘾吸烟者的纵向研究。我们将测试戒烟和复吸的候选基因；测试基因相互作用；并测试候选基因和与戒烟和复发有关的内表型之间的关联。 我们的协同计划项目采用强大的跨学科方法来提出减少烟草消费并降低随之而来的发病率和死亡率的新策略。