Functional Expression of Human Trace Amine-Associated Receptors in Mice

描述(申请人提供)：人类嗅觉为了解正常的大脑功能提供了一个独特的窗口。环境中的气味化学物质是由一个大家族的典型气味受体和一个小得多的痕量胺相关受体(TAAR)家族检测到的。在人类中只有6个完整的TAAR，而这些TAAR在许多脊椎动物中都是保守的，这表明了一个共同的、重要的功能。然而，由于目前在细胞培养系统中表达气味受体的方法的局限性，人们对人TAAR的功能特性知之甚少。在这里，我们建议通过在体内的小鼠嗅觉神经元中功能性地表达所有的人类TAAR来绕过这些问题。具体目标1是产生一组以基因为靶标的小鼠品系，其中每个人TAAR在确定的荧光标记的嗅觉神经元群体中表达。具体目标2是通过记录表达TAAR的小鼠嗅觉神经元的电生理反应来表征人类TAAR的功能。这些研究应该可以让我们第一次确定人类TAAR的配体，并应该阐明TAAR基因如何对人类嗅觉做出贡献。

DESCRIPTION (provided by applicant): Human olfaction provides a unique window into understanding normal brain function. Odorous chemicals in the environment are detected by a large family of canonical odorant receptors, and a much smaller family of Trace Amine-Associated Receptors (TAARs). There are only 6 intact TAARs in humans and the TAARs are conserved in many vertebrate species, suggesting a common, important function. However, very little is known about the functional properties of human TAARs due to the limitations of current methods to express odorant receptors in cell culture systems. Here we propose to circumvent these issues by functionally expressing all of the human TAARs in mouse olfactory sensory neurons in vivo. Specific Aim 1 is to generate a set of gene-targeted mouse strains in which each of the human TAARs is expressed in a defined population of fluorescently labeled olfactory sensory neurons. Specific Aim 2 is to functionally characterize human TAARs by recording electrophysiological responses from TAAR-expressing olfactory sensory neurons in these mice. These studies should allow us to identify for the first time ligands for the human TAARs, and should shed light on how the TAAR genes contribute to human olfaction.