Neural-Epithelial Encoding of Airway Senses

气道感觉的神经上皮编码

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要气道感觉神经元将身体和环境线索传达给大脑，包括继承气体，刺激性和肺部体积。感觉神经元与专门上皮细胞合作的亚型离散的感觉模块，具有调节相邻细胞和组织功能的潜力。但是，几乎没有了解许多神经上皮感觉位点及其基础信号的特性机制。了解气道中神经上皮通信的潜在途径将提供对呼吸的身体控制的新见解，并回答有关神经的基本问题 - 上皮相互作用。呼吸道的感觉神经很大程度上源自迷走神经，内部器官系统与大脑之间的主要感觉联系。在肺中称为神经上皮体（NEB）的神经内分泌细胞由迷走性感觉神经元支配 P2RY1-IRES-CRE，提供神经上皮导管来调节肺活性。已经提出了NEB 检测各种刺激，包括缺氧，气道拉伸和炎症提示，但对此知之甚少 NEB细胞的多样性，响应特性和物理功能。该建议将通过a）使用鼠标遗传工具访问NEB来询问NEB感觉属性， b）成像方法直接询问原位的NEB的响应，c）对感官曲目进行分类 NEB和D）剖析潜在迷走神经通路的最先进的神经科学工具。这些强大的工具将使我能够在体内有选择地激活和烧毁NEB 神经元，目标候选分子换能器，并测量这些扰动如何调节呼吸生理。我的独立研究目标将为定义分子和策划对气道刺激的感觉响应的蜂窝组件，从而有助于阐明肺部生理中的NEB。我的初步数据和自由实验室中的环境为可行性和这种方法的有效性结合了细胞和体内模型系统。自由实验室发现了迷走神经元的独特子集，介绍了一个“迷走神经图集”，以识别独特的神经元亚型，并在调查气道的感觉生物学方面的广泛专业知识。该建议的培训计划支持我的长期目的是扩大我们对感觉神经回路的理解以及它们如何转导不同的刺激为神经元和“哨兵”细胞（如NEB）之间的相互作用提供了一个新的机械框架。提出的实验方法以我的免疫学和细胞生理的背景为基础我杰出的心态团队的神经科学和肺部生理学培训。这个奖项将进一步在制定独特而独立的研究计划时，支持我的专业和科学培训。