Identification and Characterization of Oxygen-Sensing Neurons in the Lung

Stanford University, Stanford CA

Investigators

Abstract

! Pulmonary sensory neurons monitor the physiological state of our respiratory tract and regulate breathing to maintain homeostasis. This process is disrupted in many common respiratory diseases, for example asthma, COPD, and respiratory tract viral infections. Altered activation levels of these sensory neurons can cause chronic cough and other respiratory symptoms, and they may contribute to disease progression. Pulmonary sensory neurons have not been extensively characterized molecularly and their functions are still poorly understood. Classical studies have divided these sensory neurons into four classes: mechanosensitive rapidly adapting receptors, slowly adapting receptors, cough receptors, and chemosensitive C-fibers. However, recent single cell genome-wide expression profiling studies have revealed greater diversity among these neurons. One newly discovered class of pulmonary sensory neurons expresses olfactory receptor 78 (Olfr78), a lactate receptor that is part of the acute blood oxygen-sensing pathway in the carotid body. If the Olfr78- expressing pulmonary neurons function similarly in oxygen-sensing, they would be in close proximity to the site where oxygen enters the body, an excellent position to monitor the efficiency of the transfer of oxygen from air to circulating blood. I hypothesize that Olfr78-expressing airway sensory neurons, in combination with neuroepithelial bodies, form a pulmonary oxygen-sensing pathway that monitors local oxygen levels along the bronchial tree, and transmits this information to the respiratory center in the brainstem to homeostatically regulate breathing. I will use transgenic mice to visualize and manipulate the Olfr78-expessing airway sensory neurons to test this hypothesis. This study will be the first systematic structural and functional characterization of a molecularly defined subtype of pulmonary sensory neurons and will enhance our understanding of pulmonary sensory biology, and the role of these neurons in lung physiology and the symptoms and etiology of pulmonary disease. !