Project V is based on the overall hypothesis that normal lung defense mechanisms depend on the integrated actions of airway epithelia to regulate the volume and composition of airway secretions and mucociliary clearance. The project proposes to study the concept that the epithelial purinergic receptor for triphosphate nucleotides (P2U-R), coupled to the autocrine actions of ATP on the airway surface, plays a key role in the coordination of the cellular activities required to promote efficient mucociliary clearance, including ion transport, mucin secretion, and ciliary beat frequency. This proposal will also study functional and molecular aspects of key ion transport components, i.e., epithelial Na+ channels (ENaC) and Cl- transport pathways, including cAMP-mediated (CFTR) Cl- channels and Ca2+-activated """"""""alternative"""""""" Cl- channels (Cl-/a), of the airway epithelia.
The Specific Aims i nclude: 1) defining quantitative relationships between CFTR expression and function and epithelial phenotype (health and disease); 2) characterizing the expression and regulation of airway ENaC in normal subjects, and testing the hypothesis that abnormal expression and/or regulation of ENaC produces airways disease; and 3) testing the hypothesis that there is an ATP/P2U-R autocrine/paracrine system in airways, and that it is a target for novel therapies. The research strategy will emphasize studies of human tissue and in vivo studies of humans, including normal subjects and patients with cystic fibrosis, chronic bronchitis, primary ciliary dyskinesia, Liddle's syndrome (genetic defects in beta-ENaC), and pseudohypoaldosteronism (defect of mineralocorticoid-mediated Na+ transport). The protocols involve in vivo physiologic studies of Na+ and Cl- transport, and the ATP/P2U-R system. Molecular techniques that were developed to estimate the level of steady-state CFTR mRNA (quantitative RT-PCR and RPA) in nasal epithelia obtained by scrape biopsy will be extended to study the expression of ENaC subunits (alpha, beta, gamma) and P2U-R. The presence of ATP and its metabolism in airways of normal subjects and patients with airways diseases will be determined by luminometry and HPLC. Aerosolized UTP may be useful for the treatment of CF, and perhaps other airways disease, and we will test for homologous and heterologous desensitization of P2U-R in vivo approaches. Insights from these studies will clearly contribute to better understanding of normal airway epithelial physiology and the pathogenesis of inherited and acquired airways diseases, and facilitate the development of novel therapies.
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| Blackmon, R L; Kreda, S M; Sears, P R et al. (2017) Direct monitoring of pulmonary disease treatment biomarkers using plasmonic gold nanorods with diffusion-sensitive OCT. Nanoscale 9:4907-4917 |
| Esther Jr, Charles R; Turkovic, Lidija; Rosenow, Tim et al. (2016) Metabolomic biomarkers predictive of early structural lung disease in cystic fibrosis. Eur Respir J 48:1612-1621 |
| Blackmon, Richard L; Kreda, Silvia M; Sears, Patrick R et al. (2016) Diffusion-sensitive optical coherence tomography for real-time monitoring of mucus thinning treatments. Proc SPIE Int Soc Opt Eng 9697: |
| Tyrrell, Jean; Qian, Xiaozhong; Freire, Jose et al. (2015) Roflumilast combined with adenosine increases mucosal hydration in human airway epithelial cultures after cigarette smoke exposure. Am J Physiol Lung Cell Mol Physiol 308:L1068-77 |
| Esther Jr, Charles R; Coakley, Raymond D; Henderson, Ashley G et al. (2015) Metabolomic Evaluation of Neutrophilic Airway Inflammation in Cystic Fibrosis. Chest 148:507-515 |
| Åstrand, Annika B M; Hemmerling, Martin; Root, James et al. (2015) Linking increased airway hydration, ciliary beating, and mucociliary clearance through ENaC inhibition. Am J Physiol Lung Cell Mol Physiol 308:L22-32 |
| Bove, Peter F; Dang, Hong; Cheluvaraju, Chaitra et al. (2014) Breaking the in vitro alveolar type II cell proliferation barrier while retaining ion transport properties. Am J Respir Cell Mol Biol 50:767-76 |
| Esther Jr, Charles R; Boucher, Richard C; Johnson, M Ross et al. (2014) Airway drug pharmacokinetics via analysis of exhaled breath condensate. Pulm Pharmacol Ther 27:76-82 |
| Mellnik, John; Vasquez, Paula A; McKinley, Scott A et al. (2014) Micro-heterogeneity metrics for diffusion in soft matter. Soft Matter 10:7781-96 |
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