Neural-Epithelial Encoding of Airway Senses

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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.