The Program Project """"""""Pulmonary Epithelial in Health and Disease"""""""" continues to focus on how airway epithelia function in airways defense. The unifying hypothesis for the Program Project is that endogenous release of nucleotides in response to local str5essres is a major regulator of the fundamental airways defense mechanism, mucus clearance (MC) Four Projects investigate this hypothesis. Dr. Boucher's project tests, in animal models and in man, the hypothesis that (1) airway epithelia release 5' triphosphate nucleotides under basal conditions and in response to physiologic stresses; (2) autocrine regulation of ion transport is effected by nucleotide release, selectively via interaction of lumenal nucleotides with lumenal purinoceptors (P2Y-Rs); nucleotid4e release regulates MC's Dr. Stutts's project tests the hypothesis that: (1) the breakdown of nucleotides by extracellular nucleotidases forms adenosine (ADO) on airway epithelial surfaces that contributes to domain-specific, apical membrane regulation of CFTR C1- channels; (2) the adenosine A2b receptor mediates those responses and is linked to an apical membrane adenylate cyclase that forms cAMP locally in the vicinity of CFTR; (2) the concentration of cAMP in the vicinity of CFTR is regulated by membrane-specific phosphodiesterases; and (4) the reactivity of CFTR to cAMP/protein kinase A-mediated regulation is set by a membrane- specific protein kinase C. Dr. Davis's project will study the relationship between nucleotide release and the regulation of another element of mucus clearance lung defense, ciliary beat frequency (CBF), including: L (1) nucleotide and ADO regulation of CBF; (2) the topography of the membrane-specific nucleotide/ADO effector elements in CBF regulation; and (3) stress-induced nucleotide release and CBF regulation. Dr. Harden's project will study at the molecular level the major apical membrane between P2YY2-Rs and the G proteins that regulate the second messenger activities in airway epithelial cells, including the function of RGS proteins; and (2) the mechanisms of receptor desensitization/sequestration. The PPG is supported by four Cores: An Administrative Core (Core A); a Molecular and Protein Core; a Cell Culture Core and a Nucleotide and Nucleoside Measurement Core. In summary, the PPG will continue to investigate novel hypotheses about the contribution of airway epithelial to lung defense and how to improve the clearance of retained secretions in disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL034322-20
Application #
6868843
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Banks-Schlegel, Susan P
Project Start
1985-12-01
Project End
2007-01-31
Budget Start
2005-04-01
Budget End
2007-01-31
Support Year
20
Fiscal Year
2005
Total Cost
$2,301,523
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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
Ă…strand, 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

Showing the most recent 10 out of 229 publications