Studies with Nicotinic Null Mutant Mice

描述(申请人提供)：神经性烟碱胆碱能受体在整个大脑、脊髓和自主神经节都有表达。上世纪80年代，S等人克隆了11个神经元型nAChR亚基基因，其中一些亚基与神经肌肉接头(即所谓的外周型受体)表达的nAChR的A1亚基非常相似。这些类似A1的亚基被称为：A2，A3...A10，除A5外，它们为尼古丁和其他尼古丁激动剂提供结合部位。剩下的三个亚基2-4称为结构亚基。在利用表达系统(非洲爪哇卵母细胞)了解神经元nAChRs的结构和功能方面已经取得了巨大的进展。例如，表达系统的研究表明，亚基组成对生物物理和药理特性有深远的影响。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基(例如a6，？3)不容易在人工系统中表达。这些，以及其他方面的担忧，促使研究人员为几乎每一个已知的nAChR亚基开发了基因敲除(零突变)小鼠。转基因小鼠也已经被开发出来，可以表达几种功能突变，或与人类疾病相关的突变。这些转基因小鼠被用来解决以下问题：1)自然产生的(即自然的)nAChRs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？)中扮演什么角色？以及4)这些受体在调节尼古丁、酒精和其他药物成瘾方面发挥什么作用？我们拥有世界上最完整的nAChR突变小鼠集合，这些小鼠被用于几个以科罗拉多大学为中心的资助研究项目。在过去的4年里，我们已经将我们的群体从5个突变株建立到18个，并建立了一个系统，在这个系统中，我们将老鼠和/或繁殖对发送给美国的其他研究人员，最近在世界各地(到目前为止，有3个大陆)。这个应用程序请求资金，以支持这些老鼠库存的持续维护和分发。

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.