Understanding the function of trace amine-associated (TAARs)

描述（由申请人提供）：在哺乳动物中，气味由排列在鼻子的嗅觉上皮（OE）上的嗅觉感觉神经元（OSN）检测。OSN表达嗅觉受体，其是专门用于检测气味的G蛋白偶联受体。在小鼠中有大约1000个OR基因，在人类中有大约350个。大量的OR和这些OR被气味剂的组合激活允许区分无数的气味剂。然而，最近，我们的实验室已经发现了第二个家庭的14个化学感受器在小鼠的OE.Genes编码这些受体，称为微量胺相关受体（TAARs）存在于小鼠，人类和鱼类，并发现在鱼类和小鼠的OE.Like OR，个别小鼠TAARs表达在独特的子集的OSN只表达该受体。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。有趣的是，至少有三种小鼠TAAR识别尿液中发现的胺。其中一种检测与压力有关的化合物，而另外两种检测在男性和女性尿液中富集的化合物。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。首先，我们将使用钙成像来测试在组织培养细胞中表达的个体TAAR对从不同性别、年龄、生殖状态、应激水平和遗传背景的小鼠获得的小鼠分泌物的反应。接下来，我们将使用放射性TAAR探针来标记OSN轴突中的mRNA，研究TAAR信号如何在嗅球中组织。最后，我们将测试我们已经鉴定的TAAR配体是否可以刺激小鼠的生理效应。

DESCRIPTION (provided by applicant): In mammals, odorants are detected by olfactory sensory neurons (OSNs) that line the olfactory epithelium (OE) of the nose. OSNs express olfactory receptors, which are G protein-coupled receptors specialized in detecting odors. There are ~1000 OR genes in mice, and ~350 in humans. The large numbers of ORs and the combinatorial activation of those ORs by odorants allow for discrimination of myriad odorants. Recently, however, our lab has found 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 the fish and mouse OE. Like ORs, individual mouse TAARs is expressed in unique subsets of OSNs that express only that receptor. Screening of TAARs with diverse odorants revealed ligands for several TAARs, all of which are small volatile amines. Interestingly, 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. 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. First, we will use calcium imaging to test individual TAARs expressed in tissue culture cells for responses to mouse secretions obtained from mice of different sex, age, reproductive status, stress levels, and genetic background. Next, we will examine how TAAR signals are organized in the olfactory bulb using radioactive TAAR probes to label mRNAs in OSN axons. Finally, we will test whether TAAR ligands we have identified can stimulate physiological effects in mice.