Sensory receptors of the vagus nerve

项目摘要 初级感觉感受器的发现，介导我们的嗅觉，触觉，味觉， 愿景是里程碑式的成就。相比之下，迷走神经的内部感觉系统 在分子水平上研究不足，初级感觉受体在任何器官系统中都是未知的。的 迷走神经是大脑和身体之间的主要管道，控制进食行为、呼吸、血液 血压、新陈代谢、心率、恶心和咳嗽。机械感觉和化学感觉转导 迷走神经中的机制在感觉生物学中提出了极其重要的问题。感官 感受器检测由进食引起的胃扩张、主动脉弓处的血压、肺扩张 在呼吸过程中，引起咳嗽的刺激物或引起恶心的化疗药物是未知的。 了解迷走神经如何在分子水平上发出信号， 这些疾病包括肥胖、糖尿病、结肠炎、哮喘、恶心、抑郁和癫痫。 这个项目的目标是确定初级感觉受体的迷走神经，调查内部 器官状态最初的努力将集中在寻找胃和肺机械感受器以及主动脉 压力感受器，工作可以扩展到确定刺激和毒素受体，引起咳嗽， 恶心迷走神经机械感受器将使用一种新的体内神经节成像方法进行鉴定， 允许分析单个神经元对内部器官刺激的反应。体内神经节成像是 与用于分析基因功能的镶嵌功能丧失方法如RNAi相容。 解构迷走神经传入的感觉生物学将揭示自主神经如何 生理学是由神经系统控制的，并且可以为治疗设计提供新的机会。 这项提案建立在多年的基础工作之上，传统的资金无法支持 由于项目范围大，与受体识别研究相关的风险， 我在这个新领域的有限出版记录。到目前为止，我们在这一系统中的早期工作的特点是， 不同生理系统中的感觉神经元类型（Cell，2015）。资金将使新 分子水平的努力，以确定初级感觉受体蛋白，检测内部的感觉线索。

Project Summary The discoveries of primary sensory receptors that mediate our external senses of smell, touch, taste, and vision were landmark achievements. In contrast, internal sensory systems of the vagus nerve are vastly understudied at a molecular level, with primary sensory receptors unknown in any organ system. The vagus nerve is a major conduit between brain and body that controls feeding behavior, respiration, blood pressure, metabolism, heart rate, nausea, and cough. Mechanosensory and chemosensory transduction mechanisms in the vagus nerve present tremendously important problems in sensory biology. Sensory receptors that detect meal-induced stomach distension, blood pressure at the aortic arch, lung expansion during breathing, irritants that cause cough, or chemotherapeutics that induce nausea are unknown. Understanding how the vagus nerve signals at a molecular level is relevant for a wide range of clinical conditions, including obesity, diabetes, colitis, asthma, nausea, depression, and epilepsy. The goals of this project are to identify primary sensory receptors of the vagus nerve that survey internal organ state. Initial efforts will focus on finding stomach and lung mechanoreceptors as well as aortic baroreceptors, and work could be extended to identify irritant and toxin receptors that evoke cough and nausea. Vagal mechanoreceptors will be identified using a novel in vivo ganglion imaging approach that permits analysis of single neuron responses to internal organ stimuli. In vivo ganglion imaging is compatible with mosaic loss-of-function approaches like RNAi for analysis of gene function. Deconstructing the sensory biology of vagal afferents will reveal basic insights into how autonomic physiology is controlled by the nervous system, and may provide new opportunities for therapy design. This proposal builds on years of foundational work, and is not supportable by traditional funding mechanisms due to the large project scope, the risk associated with receptor-identification studies, and my limited publication record in this new field. So far, our early work in this system has characterized sensory neuron types in different physiological systems (Cell, 2015). Funding would enable new molecular-level efforts to identify primary sensory receptor proteins that detect internal sensory cues.