Identification of Functional nAChR Variants in Mice

描述(由申请人提供)： 这项提议的长期目标是鉴定近交系小鼠 表达功能不同的神经性烟碱受体亚型 Alpha3、Alpha4、Alpha6、Alpha7和Beta2亚基。这些亚基被选中 基于它们在调解导致依赖的行为中的潜在作用 尼古丁。功能不同的烟碱受体亚型的鉴定 将通过对编码基因的外显子的突变分析来启动 这些受体亚基。大约40个不同类型的近交系小鼠 基因起源将在突变筛查中进行评估。一旦突变 Screen鉴定氨基酸型小鼠的烟碱受体亚单位亚型 如果存在差异，就会产生适当的cDNA。随后，变种 尼古丁受体亚单位异构体将在体外进行评估 药理和功能特性。这些实验将导致 建立具有已知基因变异的小鼠品系目录 烟碱受体亚型功能特性。这本鼠标目录 菌株将作为一种重要的额外资源来评估 烟碱受体亚基在调节成瘾中的作用 尼古丁的作用。 据估计，美国所有过早死亡的人中有25% 各州都受到烟草使用的影响。尽管人们普遍了解人类的健康状况 吸烟的风险，大约25%的美国成年人 继续抽烟。在吸烟者中，近80%的人表示他们希望 退出，尽管只有不到5%的人成功退出。它由来已久。 尼古丁是烟草中导致依赖的主要因素，而 尼古丁在大脑中的最初作用是由尼古丁介导的 乙酰胆碱受体。然而，哪些尼古丁受体亚型介导了 人们对尼古丁的成瘾作用知之甚少。到目前为止，只有 在解决这个问题上，充其量也只是取得了一定的成功。鼠标 菌株烟碱受体的“功能”目录将导致 本提案中概述的研究将为解决以下问题提供宝贵的资源 这个问题。通过阐明哪些尼古丁受体亚型对 建立尼古丁依赖，更有效的药理作用 戒烟策略可能会被开发出来。

DESCRIPTION (Provided by applicant): It is the long-term objective of this proposal to identify inbred mouse strains that express functionally distinct isoforms of the neuronal nicotinic receptor subunits alpha3, alpha4, alpha6, alpha7, and beta2. These subunits were chosen based on their potential roles in mediating the dependence-causing actions of nicotine. Identification of functionally distinct nicotinic receptor isoforms will be initiated by mutation analysis of the exons of the genes that encode these receptor subunits. Approximately forty inbred mouse strains of distinct genetic origins will be evaluated in the mutation screen. Once the mutation screen identifies nicotinic receptor subunit isoforms in mice with amnino acid differences, the appropriate cDNAs will be generated. Subsequently, the variant nicotinic receptor subunit isoforms will be evaluated in vitro for their pharmacological and functional properties. These experiments will lead to the establishment of a catalogue of mouse strains with known variations in nicotinic receptor subtype functional properties. This catalogue of mouse strains will serve as an important additional resource to evaluate the role of the various nicotinic receptor subunits in modulating the dependence-causing actions of nicotine. It has been estimated that 25 percent of all premature deaths in the United States are due to tobacco use. Despite the widespread knowledge of the health risks of smoking, approximately 25 percent of adults in the United States continue to smoke. Among smokers, nearly 80 percent say that they would like to quit although less than 5 percent successfully do so. It is well established that nicotine is the major dependence-causing agent in tobacco and that the initial actions of nicotine in the brain are mediated by nicotinic acetyicholine receptors. However, which nicotinic receptor subtypes mediate the dependence-causing actions of nicotine is poorly understood. To date, only modest success, at best, has been achieved in resolving this issue. The mouse strain nicotinic receptor "function" catalogue that will result from the studies outlined in this proposal will add a valuable resource for addressing this issue. By elucidating which nicotinic receptor subtypes are critical for the establishment of nicotine dependence, more effective pharmacological strategies for smoking cessation may be developed.