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.