PO-1 34322, """"""""Pulmonary Epithelia in Health and Disease"""""""", will continue to investigate important aspects of normal human airway epithelial function and the role of airway epithelia in the pathogenesis of disease. The use of human airway epithelia for in vitro physiologic, cell biologic, and molecular studies, consistently interfaced with clinical investigations, will be stressed. Project IA (R. Boucher, P.I.) will investigate: (1) regulation of the basal rate of Na+ transport, including interactions with the cystic fibrosis transmembrane regulator (CFTR); and (2) acute, cell surface receptor-gated mechanisms for the regulation of ion transport, focussing on the role of intracellular Cai2+ as second messenger. Project IB (T.K. Harden, P.I.) will characterize by pharmacologic, biochemical, and ultimately molecular approaches a novel purinergic receptor (P2u) that appears to regulate ion transport and, potentially, macromolecular secretion by human airway epithelia. Project II (M.J. Stutts, P.I.) will combine studies of intact epithelia with patch clamp techniques to investigate regulation of Cl- channels. The focus will be on the relationships of Ca2+ and nucleotides, both purine and pyridine, to CFTR/Cl- channel regulation. Project III (M. Van Scott, P.I.) will investigate the basal and regulated mucin secretory activities of the human airway goblet cell. The potential expression and regulation of ion transport activities by this cell type, and its relationship to mucin secretion, will be investigated. Imaging, electrophysiologic, and cell biologic approaches are proposed to address this topic. Project IV (M.R. Knowles, P.I.) will search for novel CFTR molecular mutations expressed by """"""""variant"""""""" CF patients, identified by unusual clinical and haplotypic phenotypes. Links between mutation and phenotype will be sought by functional characterization of affected epithelia from these patients. Concepts and potential therapeutics evolved from Projects I-III will be tested for relevance in vivo by Project IV. The research program will be supported by three cores: (1) Core A: Administrative and Bioengineering (R. Boucher, P.I.); and (2) Core B: Imaging and Ultrastructure (C.W. Davis, P.I.); and (3) Core C: Tissue Culture Core (J.R. Yankaskas, P.I.). This integrated research program should yield unique insights into regulation of human airway epithelial activities essential for lung defense, including (1) mechanisms for acute cell surface receptor mediated regulation of airway secretion ionic and macromolecular composition; (2) coordination of these activities for effective clearance in the normal airway. These data, coupled with studies designed to elucidate novel mechanisms of disease, e.g., the relationship of CFTR to airway epithelial function, will be pursued with the ultimate goal being the identification of new therapeutic approaches for airways diseases.
| Schultz, André; Puvvadi, Ramaa; Borisov, Sergey M et al. (2017) Airway surface liquid pH is not acidic in children with cystic fibrosis. Nat Commun 8:1409 |
| 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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