Studies with Nicotinic Null Mutant Mice

描述（由申请人提供）： 神经元烟碱胆碱能受体在整个脑、脊髓和自主神经节中表达。11个神经元nAChR亚基基因在20世纪80年代被克隆和测序。这些亚基中的一些非常类似于在神经肌肉接头处表达的nAChR中包含的a1亚基（所谓的外周型受体）。这些类似a1的亚基被称为：a2，a3…A10和除A5之外的其它化合物提供尼古丁和其它烟碱激动剂的结合位点。剩下的三个亚基，<$2-<$4，被称为结构亚基。使用表达系统（细胞系，非洲爪蟾卵母细胞）理解神经元nAChR的结构和功能已经取得了巨大的进展。例如，表达系统研究表明，亚基组成对生物物理和药理学性质具有深远的影响。表达系统研究的价值在某种程度上受到限制，因为一些更有趣的亚基（例如α 6，β 3）不容易在人工系统中表达。这些和其他问题促使研究人员开发出几乎所有已知nAChR亚基的基因敲除（无效突变）小鼠。转基因小鼠也已经被开发，其表达几种功能获得突变或与人类疾病相关的突变。这些转基因小鼠被用于解决以下问题：1）天然存在的（即天然）nAChR的亚基组成是什么？2)这些天然受体在哪里表达？3)它们在调节大脑功能（行为？），这些受体在调节尼古丁、酒精和其他药物成瘾中起什么作用？我们有世界上最完整的nAChR突变小鼠的集合，这些小鼠被用于以科罗拉多大学为中心的几个资助研究项目。在过去的4年里，我们已经建立了我们的殖民地，从5个突变株到18个，并建立了一个系统，我们已经发送小鼠和/或育种对在美国的其他研究人员，最近在世界各地（3大洲，迄今为止）。这项申请要求提供资金，以支持继续维持和分发这些鼠种。

DESCRIPTION (provided by applicant): Neuronal nicotinic cholinergic receptors are expressed throughout the brain, in the spinal cord, and in the autonomic ganglia. Eleven neuronal nAChR subunit genes were cloned and sequenced in the 1980's. Some of these subunits closely resemble the a1 subunit that is included in the nAChR that is expressed at the neuromuscular junction (the so-called peripheral-type receptor). These a1-like subunits are called: a2, a3...a10 and, with the exception of a5, provide the binding site for nicotine and other nicotinic agonists. The three remaining subunits, ¿2-¿4, are referred to as structural subunits. Enormous progress has been made towards understanding the structure and function of neuronal nAChRs using expression systems (cell lines, Xenopus laevis oocytes). For example, expression system studies have shown that subunit composition has profound effects on biophysical and pharmacological properties. The value of expression system studies has been limited, somewhat, because some of the more interesting subunits (e.g. a6, ¿3) are not easily expressed in artificial systems. These, and other concerns, have prompted researchers to develop gene knockout (null mutant) mice for virtually every one of the known nAChR subunits. Transgenic mice have also been developed that express several gain of function mutations, or mutations that are associated with human diseases. These transgenic mice are being used to address questions such as: 1) What are the subunit compositions of naturally-occurring (i.e. native) nAChRs? 2) Where are these native receptors expressed? 3) What role do they play in modulating brain function (behavior?), and 4) What function do these receptors play in modulating addiction to nicotine, alcohol and other drugs? We have the world's most complete collection of nAChR mutant mice that are being used in several funded research projects that are centered at the University of Colorado. During the last 4 years we have built our colony from five mutant strains to 18 and have established a system where we have sent mice and/or breeding pairs to other researchers in the US and, more recently around the world (3 continents, to date). This application requests funds to support the continued maintenance and distribution of these mouse stocks.