Identification of Functional nAChR Variants in Mice

小鼠功能性 nAChR 变异体的鉴定

• 批准号: 6365366
• 负责人: JERRY A STITZEL
• 金额: $ 23.24万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6365366
• 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）： 该提案的长期目标是鉴定近交小鼠品系 表达功能不同的神经元烟碱受体亚型 亚基 alpha3、alpha4、alpha6、alpha7 和 beta2。这些亚基被选择 基于它们在调解引起依赖性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 将通过编码基因的外显子的突变分析来启动 这些受体亚基。大约四十种不同的近交系小鼠品系 遗传起源将在突变筛查中进行评估。一旦突变 筛选鉴定小鼠烟碱受体亚基亚型与氨基酸 差异，将生成适当的 cDNA。随后，变体 烟碱受体亚基亚型将在体外评估其 药理学和功能特性。这些实验将导致 建立具有已知变异的小鼠品系目录 烟碱受体亚型功能特性。本鼠标目录 菌株将作为评估作用的重要附加资源 调节引起依赖性的各种烟碱受体亚基 尼古丁的作用。 据估计，美国 25% 的过早死亡 国家是由于烟草使用。尽管健康知识已广为人知 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% 的人表示他们愿意 尽管只有不到 5% 的人成功戒烟。已经很完善了 尼古丁是烟草中主要的导致依赖性的物质，并且 尼古丁在大脑中的最初作用是由烟碱介导的 乙酰胆碱受体。然而，哪些烟碱受体亚型介导 人们对尼古丁引起依赖的作用知之甚少。迄今为止，仅 在解决这一问题方面充其量也取得了一定的成功。鼠标 菌株烟碱受体“功能”目录将产生 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。通过阐明哪些烟碱受体亚型对于 建立尼古丁依赖，药理更有效 可以制定戒烟策略。