MOLECULAR BASIS OF OLFACTORY DISCRIMINATION

哺乳动物辨别各种不同气味的机制 人们对此了解甚少。在以前的研究中，我们发现了一种新的多基因 编码数百种不同气味受体(OR)的大鼠家族 在嗅觉感觉神经元上表达的 鼻腔的上皮组织。ORS显示出特征序列 主题，但作为一个群体是非常多变的。巨大的体型和 OR家族的多样性与识别 种类繁多、结构多样的香料。我们最近发现 嗅上皮中OR基因表达的空间分布模式 这表明在大脑中可能存在着感觉信息的广泛组织 维持在轴突投射中的上皮细胞 嗅球。为了理解这一点的功能意义 对于组织来说，关键是要获得关于 个体ORs的功能特异性。一种明确的方法来解决这个问题 问题在于考察个体ORO在人类感知中的作用。通过 采取这样的方法，可能不仅可以获得信息 对于理解嗅觉信息处理很重要，但是 也能洞察人类知觉差异的基础 人口。 在这项建议中描述的研究中，我们将努力 个体OR基因与人类感知能力之间的关系 特殊的气味。我们将首先尝试分离和表征 整个人类或基因家族。在初步实验中，到目前为止，我们已经 分离了大约500个不同的人类OR基因。我们现在将搜索 有关包含我们初始筛选中遗漏的基因的其他克隆，以及 分离出它们包含的OR基因。然后OR基因将被分组 通过核酸杂交和核苷酸序列划分为亚家族 将进行分析，以调查生物多样性的程度 是人类还是家人。我们之前在老鼠身上的研究预测了集群 人类OR基因将位于许多不同的染色体位置。 为了定义人类或基因的染色体组织，我们首先 使用制备的探针将单个OR基因分配给特定的染色体 来自含有不同人类染色体的体细胞杂交系。我们 然后将OR基因簇定位到这些基因的特定区域 用荧光原位杂交技术检测染色体。最后，我们将使用 我们分离的OR基因和我们掌握的信息 在人类OR基因上累积，以分析OR的变异程度 在人类人口中的保留剧目。

The mechanisms by which mammals discriminate a vast array of diverse odors are poorly understood. In previous studies we identified a novel multigene family in rat that codes for hundreds of different odorant receptors (ORs) that are expressed on olfactory sensory neurons in the olfactory epithelium of the nasal cavity. ORs exhibit characteristic sequence motifs, but as a group are extremely variable. The tremendous size and diversity of the OR family are consistent with an ability to recognize a wide variety of structurally diverse odorants. We have recently found spatial patterns of OR gene expression in the olfactory epithelium that indicate that there may be a broad organization of sensory information in the epithelium that is maintained in the axonal projection to the olfactory bulb. In order to understand the functional significance of this organization, it is critical that information be obtained about the functional specificity of individual ORs. One clearcut approach to this problem is to examine the role of individual ORs in human perception. By taking such an approach, it may be possible to not only gain information important to an understanding of olfactory information processing, but also gain insight into the bases of perceptual differences in the human population. In the studies described in this proposal we will initiate efforts to correlate individual OR genes with the ability of humans to perceive particular odorants. We will first attempt to isolate and characterize the entire human OR gene family. In preliminary experiments, we have thus far isolated approximately 500 different human OR genes. We will now search for additional clones containing genes missed in our initial screen and isolate the OR genes that they contain. The OR genes will then be grouped into subfamilies by nucleic acid hybridization and nucleotide sequence analyses will be performed to investigate the extent of diversity in the human OR family. Our previous studies in the mouse predict that clusters of human OR genes will be located at numerous different chromosomal sites. To define the chromosomal organization of human OR genes we will first assign individual OR genes to specific chromosomes using probes prepared from somatic cell hybrid lines containing different human chromosomes. We will then localize clusters of OR genes to specific regions of these chromosomes by fluorescence in situ hybridization. Finally, we will use the isolated OR genes we have isolated and the information we have accumulated on human OR genes to analyze the extent of variation in OR repertoire in the human population.