The goal of this SCOR is to understand the normal biology of airway epithelia and the pathogenesis of disease in cystic fibrosis (CF). The molecular defect in CF is the loss of CFTR Cl channel function, which results in defective transepithelial Cl transport. Recent studies that both normal and CF airway secrete substances with antibacterial activity in the airway surface fluid. Reports that CF surface fluid has a high NaCl concentration would explain the lack of bacterial killing in CF and tie the clinic defect to the molecular effect in the Cl channel. In Project 1, Drs. Welsh and Ostedgaard will focus on regulation of CFTR Cl channels by phosphorylation of the R domain. Phosphorylation is the physiologic mechanism that controls channel activity. Their studies should provide detailed functional and three-dimensional structural information about the R domain and new insights into the regulation of CFTR. In Project 4, Drs. Zabner and Smith will focus on regulation of airway surface fluid salt concentration by CFTR Cl channels. Complementary approaches will be used to measure human airway surface fluid salt concentration both in vitro and in vivo. Novel approaches to correct the abnormal composition of airway surface fluid will also be investigated. In Project 2, Drs. McCray and Tack will investigate the biology of human beta-defensins 1 and 2 (hBD-1 and -2). These salt-inhibited defensins are anti-microbial peptides expressed in airway epithelial. Their studies will determine the cell- specific localization, this diverse beta-defensin gene family. In Project 3, Dr. Engelhardt focuses on the integrated physiology of the airways. He will specifically examine the contribution of the sub-mucosal glands to airway defense mechanisms. This project uses a novel approach to the study of mouse and tracheal xenografts in the presence and absence of sub- mucosal glands. All of the projects depend on the Cell Culture Core for tissue acquisition and development of models relevant to CF airways. Insights gained from the comprehensive approach in this SCOR will improve our understanding of the pathogenesis of CF airway disease and may lead to novel therapies.
| Bartlett, Jennifer A; Meyerholz, David K; Wohlford-Lenane, Christine L et al. (2015) Increased susceptibility to otitis media in a Splunc1-deficient mouse model. Dis Model Mech 8:501-8 |
| Bartlett, Jennifer A; Albertolle, Matthew E; Wohlford-Lenane, Christine et al. (2013) Protein composition of bronchoalveolar lavage fluid and airway surface liquid from newborn pigs. Am J Physiol Lung Cell Mol Physiol 305:L256-66 |
| Reed, Matthew D; McCombie, Barbara E; Sivillo, Aimee E et al. (2012) Safety assessment of nebulized xylitol in beagle dogs. Inhal Toxicol 24:365-72 |
| Dong, Qian; Ostedgaard, Lynda S; Rogers, Christopher et al. (2012) Human-mouse cystic fibrosis transmembrane conductance regulator (CFTR) chimeras identify regions that partially rescue CFTR-?F508 processing and alter its gating defect. Proc Natl Acad Sci U S A 109:917-22 |
| Pezzulo, Alejandro A; Starner, Timothy D; Scheetz, Todd E et al. (2011) The air-liquid interface and use of primary cell cultures are important to recapitulate the transcriptional profile of in vivo airway epithelia. Am J Physiol Lung Cell Mol Physiol 300:L25-31 |
| Schmidt, Nathan W; Mishra, Abhijit; Lai, Ghee Hwee et al. (2011) Criterion for amino acid composition of defensins and antimicrobial peptides based on geometry of membrane destabilization. J Am Chem Soc 133:6720-7 |
| Bartlett, Jennifer A; Bartlett, Jennifer; Gakhar, Lokesh et al. (2011) PLUNC: a multifunctional surfactant of the airways. Biochem Soc Trans 39:1012-6 |
| Itani, Omar A; Chen, Jeng-Haur; Karp, Philip H et al. (2011) Human cystic fibrosis airway epithelia have reduced Cl- conductance but not increased Na+ conductance. Proc Natl Acad Sci U S A 108:10260-5 |
| Fischer, Anthony J; Lennemann, Nicholas J; Krishnamurthy, Sateesh et al. (2011) Enhancement of respiratory mucosal antiviral defenses by the oxidation of iodide. Am J Respir Cell Mol Biol 45:874-81 |
| Gakhar, Lokesh; Bartlett, Jennifer A; Penterman, Jon et al. (2010) PLUNC is a novel airway surfactant protein with anti-biofilm activity. PLoS One 5:e9098 |
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