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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.

摘要嗅觉系统对气味进行编码和分析。化学物质与受体大家族成员结合根据不同的化学特征调整的蛋白质。虽然我们有一个全面的受体基因清单作为嗅觉检测的基础，我们还远远没有对嗅觉系统检测到的化学特征。这项提议利用了四个发展--记录整个嗅觉的输出的能力气味系统(犁鼻系统)，一大类结构坚硬的气味物质(硫酸盐、羧化和糖醛酸化类固醇)，一种识别具有特定配体检测的受体基因的新工具(S) Profile，以及异位表达所选受体基因并研究其功能的新工具-TO 建立第一个系统范围内对嗅觉系统如何表示化学世界的理解。这个首要目标是开发类似于锥体角色的洞察力(并具有类似的预测能力) 光感受器调谐曲线在我们对颜色视觉的理解中。该提案的具体目的是(1)通过一种新的组合编码方法揭示组合编码的新原理通过一个大的配基对犁鼻系统的覆盖率、冗余性和特异性进行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；以及(2) 通过去孤构化一个大的亚家族揭示受体序列和气味结构之间的关系犁鼻受体基因。初步数据表明，类固醇代谢物的结构刚性极大地有助于这些目标的可控性，支持对系统范围的规模。