Mapping and function of odorant receptors in the human olfactory system

人类嗅觉系统中气味受体的定位和功能

• 批准号: 8976227
• 负责人: Thomas Bozza
• 金额: $ 57.87万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8976227
• 关键词: Accounting; Afferent Neurons; Alternative Splicing; Alzheimer' s Disease; Amines; Anatomy; Animal Model; Animals; Antibodies; Antibody Specificity; Autopsy; Axon; Biological Assay; Biopsy; Calcium; Cell Line; Chemicals; Chemoreceptors; Chromosome Mapping; Code; Complement; Data; Development; Diagnostic; Disease; Electrophysiology (science); Epithelium; Excision; Exhibits; Exons; Food; Food Selections; Foundations; Future; Gene Expression; Gene Expression Profile; Gene Structure; Gene Targeting; Genes; Genetic; Health; Human; Image; Immunohistochemistry; Individual; Intervention; Introns; Label; Lesion; Ligands; Maps; Measures; Messenger RNA; Molecular; Mouse Strains; Mus; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Nose; Odorant Receptors; Odors; Olfactory Epithelium; Olfactory Pathways; Operative Surgical Procedures; Parkinson Disease; Pattern; Perception; Peripheral; Phase; Physiological; Physiology; Preparation; Process; Property; Psychophysics; Quality of life; Receptor Gene; Research; Respiratory Mucosa; Sampling; Sensory; Smell Perception; Source; Spatial Distribution; Specificity; Staging; Staining method; Stains; Structure; Structure of mucous membrane of nose; Technology; Tissue Sample; Tissues; Work; fly; in vitro Assay; in vivo; increased appetite; insight; interdisciplinary approach; member; neuroimaging; neuropathology; next generation sequencing; novel; novel diagnostics; olfactory bulb; olfactory receptor; olfactory sensory neurons; optical imaging; patch clamp; receptor; research study; response; sensory input; transcriptome; transcriptome sequencing; vapor

DESCRIPTION (provided by applicant): The sense of smell in humans is pivotal for stimulating appetite, guiding food selection, avoiding spoiled foods and noxious chemicals, and enhancing overall quality of life. Disorders in the sense of smell are commonly observed in Alzheimer's disease and Parkinson's disease, with early accumulation of neuropathological lesions in the peripheral olfactory system including sensory neurons of the nasal mucosa and their projections to the olfactory bulb. Despite the critical contributions of these structures to olfactory perceptual processing, and their widespread involvement in neurodegenerative disorders, we have only a rudimentary understanding of the molecular and cellular components of the human peripheral olfactory system. Moreover, it remains unclear whether the wealth of information available about olfaction in model organisms applies to the anatomical, physiological, and functional properties of the human olfactory system. In research proposed here, we will leverage our complementary strengths in mouse olfactory genetics (Dr. Bozza) and human olfactory neurobiology (Dr. Gottfried) to comprehensively characterize the human peripheral olfactory system with a research breadth and specificity not previously attempted. This work will exploit advanced next-generation sequencing, novel "trans vivo" gene targeting, immunohistochemistry, electrophysiology, in vivo calcium imaging, and access to human biopsy and post-mortem tissue samples, to study the expression, function, and topographical mapping of human odorant receptor genes. Specific experiments will (1) measure the expression and determine the structure of chemosensory genes including olfactory receptors (ORs) and trace amine- associated receptors (TAARs) in the human olfactory epithelium, (2) characterize the odor response profiles of human odorant receptors when expressed in mouse olfactory sensory neurons, and (3) define the spatial distribution of receptor-specific projections of human olfactory sensory neurons from the epithelium to the olfactory bulb. Together these studies will advance our understanding of the functional organization of the human olfactory system, and will set the stage for clarifying how individual chemoreceptor genes influence odor perception. Finally, by defining the functional organization of olfactory pathways in neurologically intact individuals, this work will serve as a valuable starting point for investigating the impact of neurodegenerative disease on olfactory gene expression, circuit anatomy and sensory function.

描述（由申请人提供）：人类的嗅觉对于刺激食欲，指导食物选择，避免食物和有害的化学物质以及增强整体生活质量的关键。在阿尔茨海默氏病和帕金森氏病中通常观察到嗅觉的疾病，在周围嗅觉系统中，神经病理病变早期积累，包括鼻粘膜的感觉神经元及其投影及其对嗅球的投影。尽管这些结构对嗅觉感知处理有关键的贡献，及其广泛参与神经退行性疾病，但我们对人类外周嗅觉系统的分子和细胞成分只有基本的理解。此外，尚不清楚模型生物中有关嗅觉的大量信息是否适用于人类嗅觉系统的解剖，生理和功能特性。在此处提出的研究中，我们将利用小鼠嗅觉遗传学（博士博士）和人类嗅觉神经生物学（Gottfried博士）的互补优势来全面地表征人类外围嗅觉系统，其研究广度和特异性先前未尝试。这项工作将利用高级的下一代测序，新型的“跨体内”基因靶向，免疫组织化学，电生理学，体内钙成像，以及访问人类活检和验尸后样品，以研究人类渗透受体基因的表达，功能和地形图。特定的实验将（1）测量并确定人类嗅觉上皮中（2）在人类嗅觉上皮中的表达并确定包括嗅觉受体（OR）和痕量胺相关受体（TAAR）的结构，（2）表征人类气味受体的气味反应特征在小鼠嗅觉上表达的人类气味神经元和（3）尖顶式 - 尖顶式的分布（3）从上皮到嗅球的神经元。这些研究将共同​​提高我们对人类嗅觉系统功能组织的理解，并为阐明单个化学感受器基因如何影响气味感知奠定了基础。最后，通过定义神经系统完整个体中嗅觉途径的功能组织，这项工作将成为研究神经退行性疾病对嗅觉基因表达，回路解剖学和感觉功能的影响的重要起点。