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开始吸烟（SI）和尼古丁依赖（ND）的病因有很强的影响，但我们还远远没有确定个体对ND易感性的具体遗传基础。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。我们将采用两步方法验证这些假定的风险基因：在其他人类样本中进行复制，并在ND的动物模型中证明这些基因的变异有助于ND可能涉及的神经生物学途径。我们将首先通过数据挖掘GWA数据集确定有希望的吸烟开始（SI）和ND的候选基因，并将复制选定的候选基因。使用尼古丁戒断小鼠模型，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，重点关注已经确定的临时qtl区域的菌株信息。这种方法使我们能够验证和完善尼古丁行为QTL的图谱。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确定ND的候选基因。从人类和小鼠研究中确定和优先考虑的候选基因/途径将通过药理学或遗传学操作来验证，以改变候选基因在小鼠大脑中的表达或功能，并确定尼古丁奖励和戒断模型中对行为反应的影响。

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.