Variability in the human odorant receptor repertoire

描述(申请人提供)：人类大约有400个功能性嗅觉感受器，但在这组感受器中，个体之间存在大量差异。在某些情况下，这些变异会导致部分人群中的受体不起作用。这些差异可能是嗅觉个体间差异的基础。在这里，我们建议识别气味受体的配体，产生气味受体变体的文库，并确定在变体中对气味的反应是如何改变的。这项提案中产生的数据将是我们通过检查这些自然感受器变异的知觉相关性来探索人类嗅觉的长期目标的关键一步。这些研究导致了一种假设，即嗅觉的可变性在一定程度上是由嗅觉受体的遗传功能障碍引起的，了解嗅觉受体变异和受体功能之间的联系将揭示人类气味代码的潜在逻辑。为了验证这一假说，提出了两个特定目标：特定目标1：识别具有分离多态的气味受体的配基；特定目标2：表征常见气味受体等位基因的体外功能和表达。拟议的实验进一步促进了我们的长期目标，即了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症状，包括阿尔茨海默病、帕金森氏病和精神分裂症。这项提议将为设计更有针对性的嗅觉缺陷测试提供洞察力，这些测试将临床相关信息与自然遗传变异分离。此外，拟议中的实验进一步推动了我们理解人类气味编码逻辑的长期目标。

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.