Identification of Functional nAChR Variants in Mice

小鼠功能性 nAChR 变异体的鉴定

• 批准号: 6946535
• 负责人: JERRY A STITZEL
• 金额: $ 21.96万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6946535
• 关键词: gene expression; genetic polymorphism; genetic strain; laboratory mouse; nicotine; nicotinic receptors; protein isoforms; tobacco abuse

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.

描述（由申请人提供）： 这是该提议的长期目标，是识别近交小鼠菌株 神经元烟碱受体的功能上不同的同工型 亚基Alpha3，alpha4，alpha6，alpha7和beta2。选择这些亚基 基于他们在调解引起依赖的作用中的潜在作用 尼古丁。鉴定功能不同的烟碱受体同工型 将通过对编码基因外显子的突变分析开始 这些受体亚基。大约四十个不同的近交小鼠菌株 遗传起源将在突变筛选中进行评估。一旦突变 屏幕识别氨基酸小鼠中的烟碱受体亚基同工型 差异，将生成适当的cDNA。随后，变体 烟碱受体亚基同工型将在体外评估其 药理和功能特性。这些实验将导致 建立具有已知变化的小鼠菌株目录 烟碱受体亚型功能特性。这个鼠标目录 菌株将作为评估角色的重要额外资源 调节依赖性引起的各种烟碱受体亚基 尼古丁的作用。 据估计，统一的所有早期死亡中有25％ 州是由于使用烟草所致。尽管对健康有广泛的了解 吸烟的风险，大约25％的美国成年人 继续抽烟。在吸烟者中，将近80％的人说他们想 辞职虽然不到5％成功。它已经建立了 尼古丁是烟草中主要引起依赖性的剂， 尼古丁在大脑中的初始作用是由烟碱介导的 乙酰氨酸受体。但是，烟碱受体亚型介导 尼古丁的依赖性作用知之甚少。迄今为止 充其量在解决这个问题方面取得了适度的成功。鼠标 应变烟碱受体“功能”目录，该目录将由 该提案中概述的研究将为解决 这个问题。通过阐明哪种烟碱受体亚型对于 建立尼古丁依赖性，更有效的药理 可以制定戒烟策略。