Sweet receptor T1R3 in airway glucose homeostasis and chronic rhinosinusitis - PROJECT SUMMARY: Human nasal ciliated cells express taste family 1 (T1R) sweet taste receptors that activate a unique and uncharacterized signaling pathway that regulates glucose uptake across their apical membrane. Activation of cilia T1Rs leads to arrestin-dependent signaling that increases expression of apically localized GLUT2 and GLUT10 to lower airway surface liquid (ASL) glucose. Uptake of glucose by airway epithelial cells is necessary to keep ASL glucose low to limit pathogen growth. During hyperglycemia or during epithelial barrier breakdown with inflammation, too much glucose leaks into the ASL, which is associated with increased risk of respiratory infections, particularly Staphylococcus aureus infections. We found that nasal secretion glucose is high in patients with chronic rhinosinusitis (CRS), which we initially attributed to inflammation. However, increased ASL glucose in CRS is not reduced by corticosteroids, suggesting other mechanisms are involved. Several polymorphisms in the TAS1R genes encoding T1R receptors are linked to CRS risk. We hypothesize that TAS1R polymorphisms affect ASL glucose or CRS patient outcomes. We also hypothesize that activation of T1R sweet receptors in the airway, using sugar analogues or artificial sweeteners available from food science, may enhance local innate immunity by lowering ASL glucose to help the body eradicate infections without the need for conventional antibiotics. Our goal is to elucidate T1R cilia signaling and impacts on inflammatory airway disease using both lab (Aim 1) and clinical (Aim 2) approaches. CRS will be our model inflammatory airway disease, because of its prevalence and public health impact but also because of our ability to analyze hundreds of patients during this project. In lab, we will use primary human cells cultured and differentiated at air liquid interface to define T1R signaling and downstream effects. We will use live cell imaging of cilia-localized fluorescent biosensors, pharmacology, protein knockout/knockdown, and biochemical approaches. We will also use proximity ligation and mass spec proteomics to identify interacting partners of T1Rs in cilia. In clinic, we will examine how TAS1R polymorphisms, T1R expression, and/or sweet taste intensity are associated with nasal glucose levels, CRS symptoms and outcomes, and S. aureus host-pathogen interactions. We will genotype and follow hundreds of patients and also use cells from these patients in laboratory assays in a multi-PI scientist/clinician approach. We hypothesize that T1Rs in airway ciliated cells are important and novel therapeutic targets for airway diseases to keep ASL glucose levels low in patients with diabetes or airway inflammation. Understanding cilia T1R chemosensation and the unique signaling pathways involved will shed light on how to leverage these receptors for therapeutic benefit. The independent yet inter-related aims will examine important chemosensory functions of ciliated airway cells, possibly revealing new complementary therapies for respiratory infections.
