Studies with Nicotinic Null Mutant Mice

描述(由申请人提供)： 神经元烟碱型乙酰胆碱(胆碱能)受体(NAChRs)在整个大脑和自主神经节中都有表达。从20世纪80年代中期S开始，多个神经元nAChR亚单位基因已被鉴定、克隆和测序。今天，我们知道至少有11个不同的亚基在哺乳动物中表达，其中9个亚基在小鼠的大脑中表达。神经元型nAChR被认为是五聚体配体门控离子通道，类似于特征明确的肌型nAChR。在利用表达系统了解这些受体方面已经取得了巨大的进展。例如，在非洲爪哇卵母细胞和细胞系中所做的研究表明，改变nAChRs的亚单位组成会导致这些受体的生理和药理特性发生巨大变化。人们对自然产生的受体知之甚少。目前感兴趣的问题包括：nAChRs在大脑中表达在哪里；大脑nAChRs的亚单位组成是什么；这些受体在突触传递中扮演什么角色；它们在调节大脑功能(行为)中扮演什么角色；它们在调节尼古丁成瘾过程的组成部分中扮演什么角色？在回答这些问题上，有一个工具显示出了令人难以置信的前景，那就是零突变和敲门小鼠。在过去的几年里，几个实验室已经制造出了nAChR亚单位零突变和敲击小鼠。我们已经得到了许多这样的突变动物，而且还承诺给我们更多。这些动物将被用于几个受资助的研究项目。这笔P30赠款是为了支持世界上最完整的nAChR转基因小鼠集合。支持将使我们能够进行原本几乎不可能进行的研究(考虑到目前可用的资金支持)，例如在多种遗传背景下培育老鼠和培育双突变体。我们希望，这一资源最终将提供给nAChR领域的其他研究人员。

DESCRIPTION (provided by applicant): Neuronal nicotinic acetylcholine (cholinergic) receptors (nAChRs) are expressed throughout the brain as well as in the autonomic ganglia. Starting in the mid-1980's multiple neuronal nAChR subunit genes have been identified, cloned and sequenced. Today, we know of a minimum of 11 different subunits that are expressed in mammals, and 9 of these subunits are expressed in the mouse brain. It is believed that neuronal nAChRs are pentameric ligand-gated ion channels that are similar to the well-characterized muscle-type nAChR. Tremendous progress has been made in understanding these receptors using expression systems. For example, studies done in Xenopus oocytes and cell lines indicate that altering the subunit composition of the nAChRs results in tremendous changes in the physiological and pharmacological properties of these receptors. Less is known about the naturally occurring receptors. Questions that are of current interest include: Where are the nAChRs expressed in the brain; What is the subunit composition of the brain nAChRs; What role do these receptors play in synaptic transmission; What role do they play in modulating brain function (behavior), and What is their role in modulating components of the nicotine addiction process? One tool that shows incredible promise for answering these questions is the null mutant and knockin mouse. Over the last few years nAChR subunit null mutants and knockin mice have been made in several laboratories. We have been given many of these mutant animals and more have been promised to us. These animals will be used in several funded research projects. This P30 grant has been submitted to provide support for what is the world's most complete collection of nAChR transgenic mice. Support will allow us to do studies that would otherwise be nearly impossible (given the financial support currently available) such as breeding the mice on multiple genetic backgrounds and breeding double mutants. We hope that this resource will, ultimately, be made available to other researchers in the nAChR field.