Mechanisms of chemosensory recognition

化学感应识别机制

基本信息

批准号：
10644006
负责人：
Timothy Holy
金额：
$ 44.51万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10644006
关键词：
Address Afferent Neurons Amino Acids Animals Behavioral Calcium Cells Characteristics Chemicals Code Collection Color Visions Cues Data Decision Making Detection Development Disadvantaged Ectopic Expression Equipment and supply inventories Exhibits Family Food G-Protein-Coupled Receptors Genes Goals Harvest Human Image In Vitro Individual Laboratories Length Ligand Binding Ligands Light Link Maps Measures Microscopy Modeling Molecular Molecular Conformation Mutagens Olfactory Pathways Optics Output Partner in relationship Pharmacologic Substance Physiological Population Property Proteins Receptor Activation Receptor Gene Retinal Cone Role Sensory Sequence Homology Site Smell Perception Specificity Steroids Stimulus Structure Structure-Activity Relationship Sulfate System Techniques Testing Vertebral column Volatilization Vomeronasal Systems Work blind candidate identification carboxylate carboxylation cell type chemical binding combinatorial computerized tools feature detection flexibility functional group insight member novel olfactory receptor pharmacophore predicting response receptor response screening sensory system tool vomeronasal organ

项目摘要

ABSTRACT The olfactory system encodes and analyzes odorants. Chemicals bind to members of large families of receptor proteins tuned to different chemical features. While we have a comprehensive inventory of the receptor genes that underlie olfactory detection, we are far from having a similarly comprehensive understanding of the chemical features detected by olfactory systems. This proposal leverages four developments—the ability to record the output of an entire olfactory system (the vomeronasal system), a large and structurally-rigid class of odorants (sulfated, carboxylated, and glucuronidated steroids), a new tool to identify the receptor gene(s) that have particular ligand detection profiles, and a new tool for ectopically expressing a chosen receptor gene and studying its function—to develop the first system-wide understanding of how an olfactory system represents the chemical world. The overarching goal is to develop insights analogous to (and with similar predictive power to) the role of cone photoreceptor tuning curves in our understanding of color vision. The specific aims of the proposal are (1) to reveal new principles of combinatorial coding through a system-wide analysis of the vomeronasal system’s coverage, redundancy, and specificity via a large ligand screen and quantitative analysis of the structural features required for activating each receptor; and (2) to reveal relationships between receptor sequence and odorant structure by deorphanizing a large subfamily of vomeronasal receptor genes. Preliminary data suggest that structural rigidity of steroid metabolites contributes greatly to the tractability of these aims, supporting quantitative and predictive analysis on a system-wide scale.

抽象的嗅觉系统编码和分析气味剂。化学物质与大型接收器家族的成员结合蛋白质调整为不同的化学特征。虽然我们有全面的受体基因清单这是嗅觉检测的基础，我们对嗅觉系统检测到的化学特征。该提案利用了四个发展 - 记录整个嗅觉的输出的能力系统（选民系统），一种大型且结构上的气味类（硫化，羧化和谷氨酸固定立体机构），这是一种识别具有特定配体检测的接收器基因的新工具轮廓，以及一种新的工具，用于异位表达选择的接收器基因并研究其功能 - 对嗅觉系统如何代表化学世界的第一个全系统范围的了解。这总体目标是开发与锥体相似（并具有类似的预测能力）的见解光感受器调谐曲线在我们对色觉的理解中。该提案的具体目的是（1）通过A揭示组合编码的新原则通过大型配体对选民系统的覆盖，冗余和特异性的全系统分析筛选和定量分析激活每个受体所需的结构特征；（2）到通过去畸形化的大型亚科，揭示受体序列与气形结构之间的关系选民受体基因。初步数据表明类固醇代谢产物的结构刚度对这些目标的易处理性有很大贡献，支持对系统范围范围。