Mechanisms of chemosensory recognition

化学感应识别机制

• 批准号: 10531059
• 负责人: Timothy Holy
• 金额: $ 42.42万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/10531059
• 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; G-substrate; Genes; Goals; Harvest; Human; Image; In Vitro; Individual; Laboratories; Lead; Length; Ligand Binding; Ligands; Light; Link; Maps; Measures; Microscopy; Modeling; Molecular; Molecular Conformation; Olfactory Pathways; Optics; Output; Partner in relationship; Pharmacologic Substance; Physiological; Population; Property; 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; Vomeronasal Systems; Work; base; blind; carboxylate; cell type; chemical binding; combinatorial; computerized tools; exhaustion; flexibility; functional group; insight; member; novel; olfactory receptor; pharmacophore; predicting response; receptor; response; screening; sensory system; tool; vomeronasal organ

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 嗅觉系统编码并聚集与受体大家族成员结合的化学物质。 虽然我们拥有受体基因的全面清单，但蛋白质已调整为不同的化学特征。 作为嗅觉检测的基础，我们还远未对嗅觉检测有类似的全面理解 嗅觉系统检测到的化学特征。 该提案利用了四项进展——记录整个嗅觉输出的能力 系统（犁鼻系统），一大类结构刚性的气味剂（硫酸化、羧化和 葡萄糖醛酸化类固醇），一种识别具有特定配体检测的受体基因的新工具 配置文件，以及一种用于异位表达所选受体基因并研究其功能的新工具 首次在全系统范围内理解嗅觉系统如何代表化学世界。 总体目标是开发类似于锥体作用（并具有类似预测能力）的见解 我们对色觉的理解中的感光器调谐曲线。 该提案的具体目标是（1）通过 通过大配体对犁鼻系统的覆盖范围、冗余性和特异性进行全系统分析 筛选和定量分析激活每种受体所需的结构特征；以及（2） 通过对一个大的亚科进行去孤儿化来揭示受体序列和气味结构之间的关系 犁鼻受体基因的初步数据表明类固醇代谢物的结构刚性。 极大地促进了这些目标的可处理性，支持对一个问题的定量和预测分析 全系统规模。