Mapping and function of odorant receptors in the human olfactory system

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、避免变质食物和有毒化学品以及提高整体生活质量至关重要。嗅觉障碍通常在阿尔茨海默氏病和帕金森氏病中观察到，在外周嗅觉系统中具有神经病理学损伤的早期积累，包括鼻粘膜的感觉神经元及其向嗅球的投射。尽管这些结构对嗅觉感知处理的重要贡献，以及它们在神经退行性疾病中的广泛参与，但我们对人类外周嗅觉系统的分子和细胞成分只有初步的了解。此外，目前还不清楚是否丰富的信息，可在模式生物嗅觉适用于解剖，生理和功能特性的人类嗅觉系统。在这里提出的研究中，我们将利用我们在小鼠嗅觉遗传学（Bozza博士）和人类嗅觉神经生物学（Gottfried博士）方面的互补优势，以前所未有的研究广度和特异性全面表征人类外周嗅觉系统。这项工作将利用先进的下一代测序，新的“transvivo”基因靶向，免疫组织化学，电生理学，体内钙成像，并获得人体活检和死后组织样本，研究人类气味受体基因的表达，功能和地形图。具体的实验将（1）测量人嗅觉上皮中包括嗅觉受体（OR）和痕量胺相关受体（TAAR）的化学感受基因的表达并确定其结构，（2）表征当在小鼠嗅觉感觉神经元中表达时人气味受体的气味反应谱，和（3）确定人嗅感觉神经元从上皮到嗅球的受体特异性投射的空间分布。这些研究将共同推进我们对人类嗅觉系统功能组织的理解，并将为阐明个体化学感受器基因如何影响气味感知奠定基础。最后，通过定义嗅觉通路在神经系统完整的个人的功能组织，这项工作将作为一个有价值的起点，研究神经退行性疾病对嗅觉基因表达，电路解剖和感觉功能的影响。

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.