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Molecular mechanisms of olfaction in mammals

哺乳动物嗅觉的分子机制

基本信息

批准号：
8197023
负责人：
Linda B Buck
金额：
$ 35.84万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-12-01 至 2013-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): In mammals, volatile odorants are detected by olfactory sensory neurons (OSNs) in the olfactory epithelium (OE) of the nose. In response to odorants, OSNs transmit signals to the olfactory bulb (OB) of the brain, which relays signals to the olfactory cortex (OC). The OC sends information to yet other brain areas involved in odor perception and the emotional and physiological effects of odors. Odorant detection in mice is mediated by ~1000 different odorant receptors (ORs), each expressed by a different subset of OSNs. ORs are used in a combinatorial manner to detect odorants, thereby allowing discrimination of a seemingly unlimited variety of odorants. However, we recently identified a second family of fourteen chemosensory receptors in the mouse OE. Genes encoding these receptors, called `trace amine-associated receptors' (TAARs) are present in mouse, human, and fish, and are found in both fish and mouse OE. Like ORs, individual mouse TAARs are expressed in unique subsets of OSNs that express only that receptor, and OSNs with the same TAAR are dispersed within certain OE domains. These findings indicate that there are multiple subsets of OSNs that use different TAARs rather than ORs to detect chemosensory stimuli. Screening of TAARs with diverse odorants revealed ligands for several TAARs, all of which are small volatile amines. Strikingly, at least three mouse TAARs recognize amines found in urine. One detects a compound linked to stress while the other two detect compounds enriched in male versus female urine, one reportedly a pheromone. The evolutionary conservation of the TAAR family suggests that this family may have a chemosensory function distinct from ORs. Ligands identified for TAARs thus far hint at a function associated with the detection of social cues. In the proposed studies, we will further investigate the roles played by TAARs in the mouse. To identify compounds recognized by TAARs with unknown ligands, we will screen a wide variety of amines for activation of individual TAARs. We will also use calcium imaging of TAARs expressed in a cell line to ask whether most or all TAARs detect compounds in mouse urine and, if so, whether those compounds are differentially represented in the urine of mice of different genders, ages, or genetic backgrounds. We will then examine how TAAR signals are represented in the OB. First, we will use TAAR gene probes to examine to number and positions of glomeruli that receive input from individual TAARs. Next, we will use mice coexpressing axonal reporters with selected TAARs to determine whether or not there are TAAR-specific glomeruli. Then, we will use c-Fos to examine the responses of individual TAAR glomeruli to identified TAAR ligands as well as to mouse urine from different sources. Finally, we will prepare mice that coexpress a transneuronal tracer with single TAAR genes to investigate how TAAR signals are organized in the OC.Project Narrative The mechanisms that the brain uses to perceive the world around us and to learn and remember are unknown. We will investigate the mechanisms that underlie the sense of smell to gain insight into these questions.

描述（由申请人提供）：在哺乳动物中，挥发性气味由鼻的嗅觉上皮（OE）中的嗅觉感觉神经元（OSN）检测。为了响应气味，OSN将信号传输到大脑的嗅球（OB），嗅球将信号传递到嗅觉皮层（OC）。OC将信息发送到其他涉及气味感知以及气味的情绪和生理影响的大脑区域。小鼠中的气味检测由约1000种不同的气味受体（OR）介导，每种受体由不同的OSN子集表达。OR以组合方式用于检测气味剂，从而允许区分看似无限种类的气味剂。然而，我们最近在小鼠OE中发现了第二个家族的14种化学感受受体。编码这些受体的基因，称为“痕量胺相关受体”（TAAR），存在于小鼠、人类和鱼类中，并且在鱼类和小鼠OE中都有发现。与OR一样，单个小鼠TAAR在仅表达该受体的独特OSN亚群中表达，并且具有相同TAAR的OSN分散在某些OE域中。这些研究结果表明，有多个子集的OSN使用不同的TAAR，而不是OR检测化学感觉刺激。筛选TAAR与不同的气味剂揭示了几个TAAR的配体，所有这些都是小的挥发性胺。引人注目的是，至少有三种小鼠TAAR识别尿液中发现的胺。其中一个检测到一种与压力有关的化合物，而另外两个检测到男性和女性尿液中富含的化合物，据报道，其中一个是信息素。TAAR家族的进化保守性表明该家族可能具有不同于OR的化学感受功能。到目前为止，TAAR的配体暗示了与检测社交线索相关的功能。在拟议的研究中，我们将进一步研究TAAR在小鼠中发挥的作用。为了鉴定具有未知配体的TAAR识别的化合物，我们将筛选各种各样的胺用于激活单个TAAR。我们还将使用细胞系中表达的TAAR的钙成像来询问是否大多数或所有TAAR检测小鼠尿液中的化合物，如果是这样，这些化合物是否在不同性别，年龄或遗传背景的小鼠尿液中存在差异。然后，我们将研究如何在OB中表示TAAR信号。首先，我们将使用TAAR基因探针来检查接受来自个体TAAR的输入的肾小球的数量和位置。接下来，我们将使用与选定的TAAR共表达轴突报告基因的小鼠来确定是否存在TAAR特异性肾小球。然后，我们将使用c-Fos来检查个体TAAR肾小球对鉴定的TAAR配体以及对来自不同来源的小鼠尿液的反应。最后，我们将制备共表达跨神经元示踪剂与单个TAAR基因的小鼠，以研究TAAR信号在OC中的组织方式。大脑用来感知我们周围的世界以及学习和记忆的机制是未知的。我们将研究嗅觉的机制，以深入了解这些问题。