Functional analysis of Trace Amine-Associated Receptors in vivo

描述(申请人提供)：嗅觉，嗅觉，对生活质量和整体人类健康有很大贡献。环境中的挥发性化学物质是由一个气味受体大家族检测到的，这是哺乳动物基因组中最大的基因库。气味受体家族包括三种在系统发育上截然不同的受体类型：I类和II类受体(包含1000多个基因)，以及最近发现的痕量胺相关受体家族(TAAR)(14个基因)。这个小基因家族在包括人类在内的许多哺乳动物物种中都保存得很好，这表明TAAR在气味感知中具有独特而重要的作用。据推测，TAAR对反复无常的社会信号做出反应。然而，这些受体的功能特性尚未得到很好的描述。这个建议的目的是为了确定TAAR在完整的哺乳动物嗅觉系统中的功能特性，以检验这些受体对气味(即胺)的子集产生特异性或优先反应的假设。我将产生几种基因靶向的小鼠，在这些小鼠中，表达已定义的TAAR基因的嗅觉感觉神经元及其相关的嗅球中的肾小球被荧光标记。然后，我将通过成像来自基因定义的肾小球的气味诱发活动来表征受体的反应谱。拟议中的实验将首次表征哺乳动物TAAR在体内的功能，并将作为确定这些受体如何在哺乳动物中影响气味感知的第一步。 公共卫生相关性：嗅觉对生活质量和整体人类健康至关重要。我们正在采用一种新的方法来描述一种新发现的嗅觉受体--痕量胺相关受体--如何在正常条件下检测气味。我们的方法将使我们能够第一次表征这些受体上的分子相互作用如何有助于哺乳动物的气味感知。

DESCRIPTION (provided by applicant): Olfaction, the sense of smell, contributes significantly to quality of life and overall human health. Volatile chemicals in the environment are detected by a large family of odorant receptors, the largest repertoire of genes in the mammalian genome. The odorant receptor family comprises three phylogenetically distinct types of receptors: Class I and Class II receptors (comprising over 1000 genes), and a recently discovered family of Trace Amine-Associated Receptors or TAARs (14 genes). This small gene family is well-conserved in many mammalian species including humans, suggesting that TAARs have a unique and important role in odor perception. It has been speculated that the TAARs respond to volatile social cues. However, the functional properties of these receptors are poorly characterized. The goal of this proposal is to define the functional properties of TAARs in the intact mammalian olfactory system in order to test the hypothesis that these receptors respond specifically or preferentially to a subset of odorants (i.e. amines). I will generate several strains of gene-targeted mice in which the olfactory sensory neurons expressing defined TAAR genes and their associated glomeruli in the olfactory bulb are fluorescently labeled. I will then characterize the response profiles of the receptors by imaging odor-evoked activity from the genetically defined glomeruli. The proposed experiments will characterize for the first time the function of mammalian TAARs in vivo, and will serve as the first step in determining how these receptors contribute odor perception in mammals. PUBLIC HEALTH RELEVANCE: The sense of smell is critical for quality of life and overall human health. We are taking a novel approach to characterize how odorants are detected under normal conditions by a newly discovered class of olfactory receptors, the trace amine associated receptors. Our methods will allow us to characterize for the first time how molecular interactions at these receptors contribute to mammalian odor perception.