Variability in the human odorant receptor repertoire

描述（由申请人提供）：人类有大约400种功能性嗅觉受体，但在这一组中，个体之间存在大量变异。在某些情况下，这些变异导致受体在群体的子集中无功能。这些变化可能是个体间嗅觉变化的基础。在这里，我们建议识别气味受体的配体，产生一个库的气味受体的变体，并确定如何响应气味的变化。在这个提议中产生的数据将是我们通过检查这些天然受体变化的感知相关性来探测人类嗅觉感知的长期目标的关键一步。这些研究导致了这样一种假设，即嗅觉感知的变化部分是由嗅觉受体的遗传功能障碍引起的，并且理解嗅觉受体变化和受体功能之间的联系将揭示人类气味代码的潜在逻辑。为了验证这一假设，提出了两个具体目标：具体目标1：识别具有分离多态性的气味受体配体具体目标2：表征常见气味受体等位基因的体外功能和表达。所提出的实验进一步推动了我们的长期目标，即理解人类气味编码的逻辑。 公共卫生相关性：嗅觉缺陷是许多神经退行性疾病的早期临床体征，包括阿尔茨海默病、帕金森病和精神分裂症。这一建议将为设计更有针对性的嗅觉缺陷测试提供见解，这些测试将临床相关信息与自然遗传变异分离。此外，拟议的实验进一步推动了我们的长期目标，以了解人类气味编码的逻辑。

DESCRIPTION (provided by applicant): Humans have approximately 400 functional olfactory receptors, but among this set there are a large number of variations between individuals. In some cases, these variations cause a receptor to be nonfunctional in a subset of the population. These variations likely underlie inter-individual variation in olfactory perception. Here we propose to identify ligands for odorant receptors, generate a library of odorant receptor variants and determine how responses to odorants are altered in the variants. The data generated in this proposal will be a critical step in our long-term goal to probe olfactory perception in humans by examining the perceptual correlates of these natural receptor variations. These studies lead to the hypothesis that variability in olfactory perception is caused in part by genetic dysfunction of olfactory receptors and that understanding the links between olfactory receptor variation and receptor function will reveal the underlying logic of the human odor code. To test this hypothesis, two specific aims are proposed: Specific Aim 1: Identify ligands for odorant receptors with segregating polymorphisms Specific Aim 2: Characterize the in vitro function and expression of common odorant receptor alleles. The proposed experiments further our long term goals to understand the logic of odor coding in humans. PUBLIC HEALTH RELEVANCE: Deficits in the sense of smell are an early clinical sign for a number of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and schizophrenia. This proposal will provide insight for the design of more targeted tests of olfactory deficits that dissociate clinically relevant information from natural genetic variation. In addition the proposed experiments further our long-term goals to understand the logic of odor coding in humans.