Mapping and function of odorant receptors in the human olfactory system

描述(申请人提供)：人类的嗅觉对刺激食欲、指导食物选择、避免变质的食物和有毒化学物质以及提高整体生活质量至关重要。嗅觉障碍通常见于阿尔茨海默病和帕金森氏病，早期会在周围嗅觉系统中积累神经病理损害，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知觉处理有重要贡献，并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初步的了解。此外，目前尚不清楚模型生物中有关嗅觉的丰富信息是否适用于人类嗅觉系统的解剖、生理和功能特性。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(Gottfred博士)方面的互补优势，以前所未有的研究广度和特异性来全面描述人类外周嗅觉系统。这项工作将利用先进的下一代测序技术、新型的跨体基因打靶、免疫组织化学、电生理学、体内钙成像以及获取人类活体和身体组织样本，来研究人类气味受体基因的表达、功能和地形图。具体实验将(1)测量包括嗅觉受体(ORs)和微量胺相关受体(TAARs)在内的化学感觉基因在人嗅觉上皮细胞中的表达并确定其结构；(2)表征人类气味受体在小鼠嗅觉神经元中表达时的气味反应谱；(3)确定人嗅觉神经元受体特异性投射从上皮到嗅球的空间分布。总之，这些研究将促进我们对人类嗅觉系统功能组织的理解，并将为阐明单个化学感受器基因如何影响气味感知奠定基础。最后，通过确定神经功能完整个体的嗅觉通路的功能组织，这项工作将成为研究神经退行性疾病对嗅觉基因表达、回路解剖和感觉功能的影响的有价值的起点。

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.