Cellular and Molecular Mechanisms of Olfactory Coding

描述（由申请人提供）：脊椎动物识别和区分数千种不同分子结构的气味。分子识别过程是如何完成的？气味化学结构的识别被认为是通过多个气味受体的组合整合发生的，每个受体都被调整以识别不同的分子特征。因此，通过阐明气味受体的分子特异性，我们将更好地了解信息是如何在嗅觉系统中处理的。此外，对气味识别的分子原理的了解将阐明这些受体是如何结合和区分气味配体的。在本应用中，我们重点研究了在脊椎动物嗅觉系统中表达的“C家族”G蛋白偶联受体的特性。该受体家族包括哺乳动物的粪鼻系统的信息素感应受体和鱼类嗅觉系统的氨基酸感应受体。我们的研究包括以鱼为模型系统的三个主要研究方向：(1)我们将应用和改进计算建模方法来阐明鱼嗅觉系统中表达的两种嗅觉氨基酸受体的配体-受体相互作用。一种新的“虚拟高通量”计算筛选方案也将实施，以确定这些受体的高亲和力配体。这种配体将为探测受体配体结合袋的分子结构提供有用的工具。这些研究将促进我们对这类化学感觉受体中配体识别的分子决定因素的理解。(2)利用最近开发的异源细胞和体内检测系统，我们将表征嗅觉C家族受体库中其他成员的配体调节特性。对单个受体的感受野特性的阐明反过来将使我们能够理解多个受体是如何结合使用来识别和区分气味的。(3)研究受体多聚化在嗅觉受体运输和功能中的作用。我们将测试异质受体相互作用是功能受体定位到感觉神经元顶端树突（与外部环境中的气味相互作用的部位）所必需的假设。这些研究将确定受体-受体相互作用在嗅觉感觉神经元功能受体形成中的作用，如果有的话。我们的研究将有助于阐明嗅觉编码的分子和细胞机制。嗅觉系统接收和解释来自环境的化学信号，调节进食、繁殖和其他社会行为。这些化学信号是由鼻腔初级感觉神经元中表达的受体检测到的。本研究将探讨嗅觉受体化学识别的基本原理，并阐明这些受体如何调节人类和非人类动物的重要生理和行为过程。

DESCRIPTION (provided by applicant): Vertebrates recognize and discriminate thousands of odorants of diverse molecular structure. How is this process of molecular recognition accomplished? The identification of an odorant's chemical structure is thought to occur through the combinatorial integration from multiple odorant receptors, each tuned to recognize different molecular features. Thus, by elucidating the molecular specificities of the odorant receptors we will gain a better understanding how information is processed in the olfactory system. In addition, knowledge of the molecular principles underlying odorant recognition will illuminate how these receptors are tuned to bind and discriminate odorous ligands. In this application, we focus on the properties of the "C family" G protein-coupled receptors expressed in the vertebrate olfactory system. This receptor family includes the putative pheromone-sensing receptors of the mammalian vomeronasal system and the amino acid sensing receptors of the fish olfactory system. Our studies comprise three major lines of investigation using the fish as a model system: (1) We will apply and refine computational modeling approaches to elucidate the ligand-receptor interactions in two olfactory amino acid receptors expressed in the fish olfactory system. A novel "virtual high-throughput" computational screening protocol will also be implemented to identify high- affinity ligands for these receptors. Such ligands will provide useful tools for probing the molecular architecture of the receptors' ligand binding pockets. These studies will advance our understanding of the molecular determinants underlying ligand recognition in this class of chemosensory receptor. (2) Using recently developed heterologous cell-based and in vivo assay systems, we will characterize the ligand tuning properties of other members of the olfactory C family receptor repertoire. Elucidation of the receptive field properties of individual receptors in turn will allow an understanding of how multiple receptors are used in combination to recognize and discriminate odorants. (3) We will study the role of receptor multimerization in olfactory receptor trafficking and function. We will test the hypothesis that heteromeric receptor interactions are required for the localization of functional receptors to the sensory neuron's apical dendrite - the site of interaction with odorants in the external environment. These studies will establish what role, if any, receptor- receptor interactions play in the formation of functional receptors in the olfactory sensory neuron. Together our studies will help to elucidate the molecular and cellular mechanisms of olfactory coding. PUBLIC HEALTH RELEVANCE The olfactory system receives and interprets chemical cues from the environment that regulate feeding, reproduction, and other social behaviors. These chemical cues are detected by receptors expressed in the primary sensory neurons of the nose. The studies proposed in the present application will investigate the principles underlying chemical recognition by olfactory receptors, and will illuminate how these receptors regulate important physiologic and behavioral processes in humans and non-human animals.