ROLE OF CHRNA5 IN MODULATING SENSITIVITY TO NICOTINE IN MICE

Bierut和他的同事最近证明了编码阿尔法病毒的基因的一个多态性 CHRNA5亚基与人体对尼古丁的依赖有关。此外，我们集团还拥有 证明了含有α-乙酰胆碱受体的nAChR参与了nAChR功能的调节，并证明了 编码小鼠阿尔法蛋白亚单位的基因的多态与 对尼古丁的高剂量效应敏感。尽管如此，烟碱型乙酰胆碱受体的作用 (NAChR)α亚基在调节药物成瘾过程和脑功能中的作用尚不清楚。在……里面 根据COGEND计划项目的总体目标，即识别基因， 环境特征，以及使个体易于或保护其免受疾病侵袭的生物机制 尼古丁依赖的持久性，我们计划用三只小鼠的基因进行一系列实验 解决CHMAS/ALPHA可能有助于的基本机制的CHRNAS模型(S) 尼古丁成瘾。我们将使用的三种鼠标模型包括！)删除了chrna S的小鼠 2)自然发生的ChmaS等位基因变异已被交换的小鼠 两个近交系小鼠(C3.D2Chma5和D2.C3Chma5)之间；3)人类非同义词 SNP已被引入(CHMAS D398N Kl)。使用这些鼠标模型，我们将1)定义 脑区和神经递质系统，其功能由含有nAChRs的α蛋白调节；以及 2)确定chrna S在调节可以在被认为是 成瘾过程的组成部分，包括药物强化、药物厌恶、耐受性发展 和戒烟。因为chrnas对药物滥用相关表型的影响可能发生在 青春期和/或成年期，这两个年龄组都将接受nAChR功能和行为的评估。 与公共健康相关：众所周知，基因在决定一个人是否 会成为一名吸烟者。在这一建议中，一种名为chrna S的特定基因的遗传差异的影响 将在老鼠身上进行研究，以确定这种基因可能如何影响个体对成瘾性药物的反应 烟草中的物质尼古丁。这项研究应该提供信息，以提高我们对 基因如何影响含尼古丁产品的使用。

Bierut and colleagues recently demonstrated that a polymorphism in the gene that encodes the alphas subunit, CHRNA5, is associated with nicotine dependence in human subjects. In addition, our group has shown that alphaS-containing nAChRs are involved in modulating nAChR function and also demonstrated that a polymorphism in the gene that encodes the mouse alphas subunit, ChrnaS, is associated with sensitivity to the high dose effects of nicotine. Nonetheless, the role of the nicotinic acetylcholine receptor (nAChR) alphas subunit in modulating the drug addiction process and brain function is poorly understood. In accordance with the overall goals of the COGEND Program Project, which are the identification of genes, environmental features, and biological mechanisms that predispose or protect individuals from the onset and persistence of nicotine dependence, we plan to conduct a series of experiments using three mouse genetic models of ChrnaS to address the basic mechanism(s) through which ChmaS/alphaS might contribute to nicotine addiction. The three mouse models we will utilize include!) Mice in which ChrnaS has been deleted (ChrnaS KO mice); 2) Mice in which naturally-occurring allelic variants of ChmaS have been exchanged between two inbred mouse strains (C3.D2Chma5 and D2.C3Chma5); and 3) Mice in which the human nonsynonymous SNP has been introduced (ChmaS D398N Kl). With these mouse models, we will 1) define the brain regions and neurotransmitter systems whose function is modulated by alphas containing nAChRs; and 2) determine the role of ChrnaS in regulating behaviors that can be modeled in mice that are thought to be components of the addiction process, including drug reinforcement, drug aversion, tolerance development and withdrawal. Because the influence of ChrnaS on drug abuse related phenotypes could occur in adolescence and/or adulthood, both age groups will be assessed for nAChR function and behavior. Relevance to public health: Genes are known to play a significant part in determining whether an individual will become a smoker. In this proposal, the influence of a genetic difference in a specific gene called ChrnaS will be studied in mice to determine how this gene might affect how an individual responds to the addictive substance in tobacco, nicotine. This study should provide information that will improve our understanding of how genes influence the use of nicotine-containing products.