Neural-Epithelial Encoding of Airway Senses

项目摘要/摘要 呼吸道感觉神经元将生理和环境信号传递给大脑，包括吸入 气体、刺激物和肺容量。感觉神经元亚型与特化上皮细胞协同形成 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，几乎没有 了解许多神经上皮感觉部位的特性及其潜在的信号传递 机械装置。了解呼吸道神经-上皮交流的潜在途径将提供 对呼吸的生理控制的新见解和回答关于神经的基本问题- 上皮性相互作用。呼吸道的感觉神经主要来自迷走神经， 内部器官系统和大脑之间的主要感官联系。在肺里，一簇簇 神经内分泌细胞称为神经上皮体(NEB)，由迷走神经感觉神经元支配，标记为 P2ry1-res-cre，为调节肺活动提供一条神经上皮管道。已经提出了NEBS 以检测各种刺激，包括缺氧、呼吸道伸展和炎症线索，但对 NEB细胞的多样性、反应特性和生理功能。 这项提议将通过a)使用小鼠遗传工具获得NEB， B)直接就地询问NEBs反应的成像方法，c)编目感觉曲目 以及d)最先进的神经科学工具来解剖潜在的迷走神经回路。这些强大的 工具将允许我选择性地激活和消融活体中的NEB，远程控制相关的迷走神经感觉 神经元，作为候选分子转导的目标，并测量这些扰动如何调节呼吸 生理学。我的独立研究目标将提供机械洞察力来定义分子和 协调对呼吸道刺激的感觉反应的细胞组件，从而帮助阐明 肺生理学中的NEBS。 我的初步数据和Liberles实验室的环境为可行性和 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亚群，描绘了一份“迷走神经图谱”，以确定独特的神经元亚型，以及 在调查呼吸道感觉生物学方面具有丰富的专业知识。这项拟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以及它们如何传递不同刺激的理解，从而 为神经元和前哨细胞之间的相互作用提供了一个新的机制框架，如NEBs。这个 建议的实验方法以我在免疫学和细胞生理学方面的背景为基础，采用新的 我优秀的导师团队提供了神经科学和肺生理学方面的培训。这一奖项将进一步 支持我的专业和科学培训，因为我制定了一个独特的和独立的研究计划。

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.