Neural-Epithelial Encoding of Airway Senses

气道感觉的神经上皮编码

• 批准号: 10490251
• 负责人: Michael Stephen Schappe
• 金额: $ 6.76万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10490251
• 关键词: Ablation; Afferent Neurons; Air; Atlases; Award; Biological Models; Biology; Brain; Breathing; Cataloging; Cell physiology; Cells; Chemicals; Code; Communication; Cues; Data; Detection; Environment; Epithelial; Epithelial Cells; Esthesia; Gases; Genetic; Goals; Hypoxia; Image; Immunology; In Situ; Inflammatory; Inhalation; Ion Channel; Irritants; Knockout Mice; Logic; Lung; Measures; Mediating; Mentorship; Methodology; Microscopy; Molecular; Mus; Neural Pathways; Neuroendocrine Cell; Neuroepithelial; Neuroepithelial Bodies; Neurons; Neurosciences; Organ; Pathway interactions; Physiological; Physiology; Piezo 2 ion channel; Population; Positioning Attribute; Preparation; Property; Regulation; Reporter; Research; Respiration; Respiratory System; Respiratory physiology; Role; Secretory Cell; Sensory; Sensory Receptors; Sentinel; Signal Transduction; Site; Specialized Epithelial Cell; Stimulus; Stretching; Surveys; Taste Perception; Tissues; Training; Transducers; Vagus nerve structure; Viral; Work; airway epithelium; body system; cell type; cellular transduction; designer receptors exclusively activated by designer drugs; hormonal signals; imaging approach; in vivo; in vivo Model; insight; lung volume; mechanical stimulus; mouse genetics; nerve supply; neural circuit; neuronal circuitry; neurosensory; neurotransmitter release; optogenetics; preservation; programs; pulmonary function; relating to nervous system; remote control; respiratory; respiratory challenge; respiratory reflex; response; sensor; sensory input; sensory stimulus; stressor; tool; transcriptomics

PROJECT SUMMARY/ABSTRACT Airway sensory neurons communicate physiological and environmental cues to the brain, including inhaled gases, irritants, and lung volume. Subtypes of sensory neurons cooperate with specialized epithelial cells to form discrete sensory modules, with the potential to regulate neighboring cells and tissue function. Yet, little is understood about the properties of many neural-epithelial sensory sites and their underlying signaling mechanisms. Understanding the underlying pathways of neural-epithelial communication in the airways will offer new insights into the physiological control of respiration and answer fundamental questions about neural- epithelial interactions. Sensory innervation of the respiratory tract is largely derived from the vagus nerve, the major sensory connection between the internal organ systems and the brain. In the lung, clusters of neuroendocrine cells termed neuroepithelial bodies (NEBs) are innervated by vagal sensory neurons marked by P2ry1-ires-cre, providing a neuro-epithelial conduit to modulate pulmonary activity. NEBs have been proposed to detect various stimuli, including hypoxia, airway stretch, and inflammatory cues, but little is known about the diversity, response properties, and physiological functions of NEB cells. This proposal will interrogate NEB sensory properties by a) gaining access to NEBs using mouse genetic tools, b) imaging approaches to directly interrogate the responses of NEBs in situ, c) cataloging the sensory repertoire of NEBs, and d) state-of-the-art neuroscience tools to dissect the underlying vagal neurocircuitry. These powerful tools will allow me to selectively activate and ablate NEBs in vivo, remotely control associated vagal sensory neurons, target candidate molecular transducers, and measure how these perturbations regulate respiratory physiology. My independent research aims will provide mechanistic insight into defining both the molecular and cellular components that orchestrate sensory responses to airway stimuli, thereby helping illuminate the role of NEBs in pulmonary physiology. My preliminary data and the environment in the Liberles Lab provide strong evidence for the feasibility and validity of this approach, which combines cellular and in vivo model systems. The Liberles Lab has discovered distinct subsets of vagal sensory neurons, profiled a “vagal atlas” to identify unique neuronal subtypes, and extensive expertise in surveying sensory biology in airways. This proposed training plan supports my long-term goal to expand our understanding of sensory neural circuits and how they transduce distinct stimuli, thereby providing a new mechanistic framework for interactions between neurons and ‘sentinel’ cells, like NEBs. The proposed experimental approaches build on my background in immunology and cellular physiology with new training in neuroscience and pulmonary physiology from my outstanding mentorship team. This award will further support my professional and scientific training as I develop a unique and independent research program.

项目总结/摘要 呼吸道感觉神经元将生理和环境线索传达给大脑，包括吸入 气体、刺激物和肺容量。感觉神经元的亚型与特化上皮细胞合作形成 离散的感觉模块，具有调节邻近细胞和组织功能的潜力。然而， 了解许多神经上皮感觉部位的特性及其潜在的信号传导 机制等了解气道中神经上皮细胞通讯的潜在途径将提供 对呼吸生理控制的新见解，并回答有关神经的基本问题， 上皮相互作用呼吸道的感觉神经支配主要来源于迷走神经， 内部器官系统和大脑之间的主要感觉联系。在肺部， 被称为神经上皮小体（NEB）的神经内分泌细胞受迷走神经感觉神经元支配， p2 ry 1-ires-cre，提供调节肺活动的神经上皮管道。已提议设立NEB 检测各种刺激，包括缺氧，气道伸展和炎症线索，但对这些刺激知之甚少。 NEB细胞的多样性、反应特性和生理功能。 该提案将通过a）使用小鼠遗传工具获得NEB， B）直接询问原位NEB反应的成像方法，c）对感觉库进行编目 和d）最先进的神经科学工具来解剖潜在的迷走神经回路。这些强大 工具将允许我在体内选择性地激活和消融NEB，远程控制相关的迷走神经感觉 神经元，目标候选分子转换器，并测量这些扰动如何调节呼吸 physiology.我的独立研究目标将提供机制的见解，以定义分子和 协调对气道刺激的感觉反应的细胞成分，从而帮助阐明 肺生理学中的NEB。 我的初步数据和Liberles实验室的环境为可行性提供了有力的证据， 这种方法的有效性，它结合了细胞和体内模型系统。利伯勒斯实验室发现 迷走神经感觉神经元的不同子集，描绘“迷走神经图谱”以识别独特的神经元亚型，以及 在调查气道感觉生物学方面拥有丰富的专业知识。这份培训计划支持我的长期发展。 我们的目标是扩大我们对感觉神经回路的理解，以及它们如何识别不同的刺激，从而 为神经元和“哨兵”细胞（如NEB）之间的相互作用提供了一个新的机制框架。的 提出的实验方法建立在我的免疫学和细胞生理学背景上， 在神经科学和肺生理学方面的培训。该奖项将进一步 支持我的专业和科学培训，因为我开发了一个独特的和独立的研究计划。