Genes and molecular pathways in nicotine dependence and withdrawal

描述（由申请人提供）：尽管有证据表明遗传因素对吸烟开始（SI）和尼古丁依赖（ND）的病因有很强的贡献，但我们远未确定个体对ND易感性的特定遗传基础。 该项目旨在加深我们对基因如何导致尼古丁依赖（ND）风险的理解，旨在最大限度地利用这组研究人员在复杂的人类遗传学，动物遗传学和尼古丁药理学方面相对独特和互补的技能。 我们将使用两步方法验证这些推定的风险基因：在其他人类样本中复制，并在ND动物模型中证明这些基因中的变异有助于可能参与ND的神经生物学途径。 我们将首先通过数据挖掘GWA数据集来识别有希望的吸烟启动（SI）和ND候选基因，并将所选候选基因进行复制。 使用尼古丁戒断的小鼠模型，我们将使用最近开发的扩展BXD RI小鼠品系面板来表征与ND相关的行为QTL，重点关注为已经确定的临时QTL区域提供信息的品系。 这种方法使我们能够验证和完善我们的尼古丁行为QTL的定位。 此外，我们将通过结合这些BXD RI小鼠品系的表达和行为遗传学分析来鉴定ND的候选基因。 将通过药理学或遗传操作验证从人类和小鼠研究中识别和优先排序的候选基因/途径，以改变小鼠大脑中候选基因的表达或功能，并确定对尼古丁奖赏和戒断模型中行为反应的影响。

DESCRIPTION (provided by applicant): Despite evidence of strong genetic contributions to the etiology of smoking initiation (SI) and nicotine dependence (ND), we are far from identifying the specific genetic basis of individual susceptibility to ND. This project - to deepen our understanding of how genes contribute to risk for nicotine dependence (ND) - has arisen as an effort to utilize maximally the relatively unique and complementary set of skill of this group of investigators in complex human genetics, animal genetics and nicotine pharmacology. We will validate these putative risk genes using a two-step approach: replication in other human samples and the demonstration in animal models of ND that variants in these genes contribute to neurobiological pathways likely involved in ND. We will first identify promising candidate genes for smoking initiation (SI) and ND by data-mining GWA datasets and the selected candidates will be replicated. Using a mouse model of nicotine withdrawal, we will characterize behavioral QTLs relevant for ND using a recently developed expanded BXD RI mouse strain panel, focusing on strains informative for already identified areas of provisional QTLs. This approach allows us to both validate and refine our mapping of the nicotine behavioral QTL. Furthermore, we will identify candidate genes for ND by combining expression and behavioral genetics analyses in these BXD RI mouse strains. Candidate genes/pathways identified and prioritized from human and mouse studies will be validated by pharmacological or genetic manipulations to alter expression or function of candidate genes in mouse brain and determine effects on behavioral responses to in models of nicotine reward and withdrawal.