Studies with Nicotinic Null Mutant Mice

描述（由申请人提供）：神经元尼古丁胆碱能受体在整个大脑、脊髓和自主神经节中表达。在20世纪80年代，11个神经元nAChR亚基基因被克隆并测序。其中一些亚基与在神经肌肉连接处表达的nAChR中包含的a1亚基（即所谓的外周型受体）非常相似。这些类似a1的亚基被称为：a2， a3…A10和，除a5外，为尼古丁和其他尼古丁激动剂提供结合位点。其余三个亚基，¿2-¿4，被称为结构亚基。在利用表达系统（细胞系，非洲爪蟾卵母细胞）了解神经元nachr的结构和功能方面取得了巨大进展。例如，表达系统研究表明，亚基组成对生物物理和药理学特性具有深远的影响。表达系统研究的价值在某种程度上是有限的，因为一些更有趣的亚单位（例如a6，¿3）不容易在人工系统中表达。这些问题以及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（零突变）小鼠。转基因小鼠也被开发出来，表达几种功能突变的增益，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（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）中起什么作用？ 4)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突变小鼠集合，这些小鼠被用于科罗拉多大学的几个资助研究项目。在过去的4年里，我们已经建立了从5个突变株到18个突变株的菌落，并建立了一个系统，我们将小鼠和/或繁殖对发送给美国的其他研究人员，最近在世界各地（迄今为止的3大洲）。此申请请求资金，以支持继续维护和分发这些鼠标库存。

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.