Role of taste signaling in airway epithelial function

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 DESCRIPTION (provided by applicant): In this project, we aim to study the role of chemosensory detection in inflammatory diseases of the nose and sinuses. These diseases-in particular rhinitis and rhinosinusitis-are extremely prevalent and bothersome disorders. Recently, basic science research has established a mechanism for airway inflammation in rodents using taste signaling pathways in specialized cells known as solitary chemosensory cells (SCCs). We have recently found these cells in human tissues, and our long-term objective is to examine the role of SCCs in human inflammatory diseases of the sinonasal cavity. Our first aim is to determine where these cells are located in the sinonasal cavity, using immunostaining techniques on tissue obtained from cadavers and human subjects. We expect to see a moderate abundance and uneven distribution based on our preliminary experiments. SCCs are a novel population of cells yet to be studied in human respiratory epithelium, and understanding the distribution of these cells will facilitate the ability to biopsy them for future research. In the second aim, we will examine the distribution of taste receptors based on anatomic location and disease state. There are 25 human bitter taste receptors, and we expect to see that some of these are found more often in the front of the nose, and others will be found deeper in the sinuses. Similarly, some may be more expressed in disease states such as allergic rhinitis and chronic rhinosinusitis. To test this hypothesis, we will evaluate the relativ expression of these bitter taste receptors in different areas of the airway, and compare healthy to diseased patient tissues. We will test classic irritants and pathogens against receptors identified in human patients to determine if these receptors are able to detect the potential stimulants. These findings will establish the connection of chemosensory detection to the human diseases of rhinitis and rhinosinusitis, and open the door for novel therapies to treat these highly burdensome chronic diseases. In the third and final aim, we will evaluate if taste transduction is required to regulate the bacterial colonization of the mucosal surface. The microbiome varies markedly between people, yet the host factors that influence bacterial colonization are poorly understood. Prior evidence in rodents and humans has shown that SCCs and bitter taste mechanisms are able to detect respiratory pathogens and initiate a response to kill and clear these bacteria. In this aim, we will use modern DNA sequencing techniques to examine the airway surface bacterial communities from (1) mice that lack the ability to use bitter taste pathways, and (2) humans that have a genetic bitter receptor defect (T2R38). Our preliminary results from human sinuses suggest a role for these pathways; confirmation of this would represent a truly innovative finding that establishes a new relevance for chemosensory transduction.