Understanding the function of trace amine-associated (TAARs)

描述(申请人提供)：在哺乳动物中，气味是由排列在鼻子嗅觉上皮(OE)的嗅觉神经元(OSN)检测到的。OSN表达嗅觉受体，这是一种G蛋白偶联受体，专门用于检测气味。小鼠大约有1000个OR基因，人类大约有350个。大量的ORs和这些ORs的组合被气味物质激活，使得可以区分无数的气味物质。然而，最近，我们的实验室在小鼠的OE中发现了第二个家族的14个化学感受器。编码这些受体的基因被称为示踪胺相关受体(TAAR)，存在于小鼠、人类和鱼中，在鱼和小鼠的OE中也发现了这种受体。与ORs一样，单个小鼠的TAAR在仅表达该受体的OSNs的独特子集中表达。对含有不同气味的TAAR的筛选显示，几种TAAR的配体都是小挥发性胺。有趣的是，至少有三个老鼠TAAR识别尿液中的胺。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。TAAR家族的进化保守性提示该家族可能具有不同于ORS的化学感觉功能。到目前为止，为TAAR识别的配体暗示了一种与社会线索检测相关的功能。在拟议的研究中，我们将进一步研究TAAR在小鼠中所起的作用。首先，我们将使用钙成像来测试组织培养细胞中表达的单个TAAR对不同性别、年龄、生殖状态、应激水平和遗传背景的小鼠分泌物的反应。接下来，我们将使用放射性TAAR探针标记OSN轴突中的mRNAs，研究TAAR信号在嗅球中是如何组织的。最后，我们将测试我们已经确定的TAAR配体是否可以刺激小鼠的生理效应。 与公共卫生相关：TAAR是一个新发现的受体家族，从鱼类到人类都是保守的，可能会探测到社会线索。因此，在老鼠身上的这项工作将确定TAAR识别的某些气味线索是否可以在情感和生理上引起先天反应，这意味着在人类社会背景下感知气味线索的新能力。

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. PUBLIC HEALTH RELEVANCE: TAARs are a newly found family of receptors conserved from fish to humans that may detect social cues. Hence, this work in mice will ascertain whether certain odor cues recognized by TAARs can cause innate responses in emotion and physiology, implicating a novel ability to sense odor cues in human social contexts.