The Genetic Basis of Specific Anosmia

特异性嗅觉丧失的遗传基础

• 批准号: 7494438
• 负责人: Joel D Mainland
• 金额: $ 5.41万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7494438
• 关键词: Address; Affect; Agonist; Animal Model; Anosmia; Behavior; Biological Models; Characteristics; Chemical Structure; Chemicals; Color; Color blindness; Detection; Disruption; Frequencies; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Human; Individual; Investigation; Ligands; Link; Maps; Molecular Biology; Molecular Structure; Mutation; Neural Pathways; Neurosciences; Numbers; Odorant Receptors; Odors; Open Reading Frames; Perception; Phenotype; Play; Population; Problem Solving; Psychophysiology; Receptor Cell; Receptor Gene; Relative (related person); Retinal Cone; Role; Scientist; Site; Smell Perception; Stimulus; System; Testing; Thinking; Translating; Variant; Vision; Visual system structure; base; falls; fitness; hyposmia; in vitro Assay; isovaleric acid; molecular recognition; novel; olfactory receptor; physical property; receptor; receptor binding; trait

DESCRIPTION (provided by applicant): A fundamental problem in neuroscience is mapping physical properties of a stimulus to perceptual characteristics. In vision, wavelength translates into color; in audition frequency translates into pitch. By contrast, the mapping from chemical structure to olfactory percept is unknown. In other words, there is not a scientist or perfumer in the world who can view a novel molecular structure and predict how it will smell. The first step in solving this problem is to link variation in the olfactory receptor to variation in perception. One form of perceptual variation is specific anosmia, which describes an individual with a lowered sensitivity to a specific molecule despite otherwise intact olfactory abilities. This phenotype is thought to reflect polymorphisms in the olfactory receptor genes, much as color-blindness reflects a deficiency in one of the cone receptors in the visual system. Here I propose to study the genetic basis of olfactory perception through the investigation of specific anosmia. This proposal intends to examine how variation in olfactory receptor genes underlies variation in olfactory perception. In Aim 1 I will use a heterologous expression system of human odorant receptors to screen for candidate odorant receptors that respond to isovaleric acid and pentadecalactone-two odorant chemicals implicated in specific anosmia In Aim 2 I will correlate the psychophysical detection threshold clusters of specific anosmia with the underlying receptor's genotype. By focusing on phenotypes that are both easy to psychophysically characterize and involve few genes, we hope to provide the first links between genetic variation and perceptual phenotype in the olfactory system. . Understanding how specific anosmia occurs would allow either specific anosmia or hyposmia to be artificially induced to eliminate or enhance specific odors by producing agonists and antagonists for certain receptor types. In addition, olfaction represents an ideal model system for understanding the genetic basis of multi-factor traits. A number of olfactory genes do not appear to be essential for human fitness, which has allowed a large amount of genetic variation in the genotype. This large natural variation in a model animal (humans) that can clearly describe the perceptual consequences of genotypic variation allows for careful study of the link between genotype and phenotype.

描述(由申请人提供)：神经科学中的一个基本问题是将刺激的物理属性映射到感知特征。在视觉中，波长转化为颜色；在听觉中，频率转化为音调。相比之下，从化学结构到嗅觉的映射是未知的。换句话说，世界上没有一位科学家或香水师能够观察到一种新颖的分子结构并预测它的气味。解决这个问题的第一步是将嗅觉感受器的变化与感知的变化联系起来。知觉变异的一种形式是特异性嗅觉障碍，它描述了一个人对特定分子的敏感度降低，尽管其他方面嗅觉能力都没有变化。这种表型被认为反映了嗅觉受体基因的多态，就像色盲反映了视觉系统中的一个锥体受体的缺陷一样。在这里，我建议通过对特异性嗅觉缺失的研究来研究嗅觉的遗传学基础。这项提议旨在研究嗅觉受体基因的变异是如何导致嗅觉的变异的。在目标1中，我将使用人类气味受体的异源表达系统来筛选对异戊酸和十五内酯有反应的候选气味受体。在目标2中，我将把特定嗅觉缺失的心理物理检测阈值簇与潜在受体的基因相关联。通过关注那些既易于心理生理表征又涉及较少基因的表型，我们希望在嗅觉系统中提供遗传变异和知觉表型之间的第一个联系。。了解特定的嗅觉丧失是如何发生的，将允许人工诱导特定的嗅觉丧失或低嗅觉，通过为某些受体类型产生激动剂和拮抗剂来消除或增强特定的气味。此外，嗅觉是理解多因素性状遗传基础的理想模型系统。许多嗅觉基因似乎对人类的健康并不是必不可少的，这使得这种基因在基因上产生了大量的变异。在模型动物(人类)中，这种巨大的自然变异可以清楚地描述基因变异的感知后果，这使得仔细研究基因和表型之间的联系成为可能。