The liquids that line the surface of the lung are critical for the maintenance of lung health. Focusing on CFTR, ENaC, and extracellular purines/purinoceptors, the PPG proposes to elucidate the molecular mechanisms that 1) regulate pulmonary surface liquid at local levels and 2) integrate airway and alveolar pulmonary surface liquid physiologies. To accomplish these goals, the PPG requires four Projects. Project I (Dynamics and Thermal Stability in CFTR Function and Dysfunction, J. R. Riordan, Ph.D., P.l.) proposes to study the mechanisms that confer temperature stability to wild-type CFTR, and, importantly, the temperature instability at physiologic temperatures of ?F508 CFTR. Project II (CFTR-ENaC Regulatory and Structural Interactions in Human Airway Epithelia, M.J. Stutts, Ph.D., P.l.) proposes to study the molecular basis for the regulatory relationship between CFTR and ENaC in airway epithelia at the structural, functional, and the regulatory levels. Project III (Purinergic Control of CFTR-ENaC Interactions in Alveolar Epithelia, R.C. Boucher, M.D., P.l.) proposes to study purinoceptor regulation of the CFTR-ENaC interrelationship on alveolar surfaces, focusing on the dominance of purinoceptor inhibition of ENaC in controlling the direction of alveolar liquid flow. Project IV (Mechanisms and Consequences of Nucleotide Release in the Lung, E. R. Lazarowski, Ph.D., P.l.) will investigate the mechanisms, regulation, and consequences of nucleotide release in airway epithelia, investigating the relative roles of vesicular vs. conductive release paths in health and their contribution to the pathogenesis of major airways diseases. The PPG Projects are supported by three Cores: an Administrative Core;a Cell Culture Core;and a Molecular Biology Core. By focusing on three major themes, i.e., CFTR, ENaC, and purinoceptor ligand-receptor interactions, from molecular to systems biology length scales, the PPG proposes to 1) generate a detailed molecular understanding of the regulation of Ion channel number/activity for local pulmonary surface liquid homeostasis and 2) integrate these activities over the entire surface of the lung to provide the framework for understanding normal physiology, disease pathogenesis, and design of novel therapies for major human lung diseases.

Public Health Relevance

The liquids lining pulmonary surfaces are at the interface between the human body and the environment. An understanding of integrated surface liquid homeostatic physiology is vital to understand how the lung confronts environmental stresses, and how the lung fails in diseases of pulmonary surface liquid depletion or excess. In particular, elucidation of how the lung fails in these diseases should reveal novel therapeutic strategies to address major human lung diseases, including cystic fibrosis, COPD, and ARDS.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Banks-Schlegel, Susan P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Internal Medicine/Medicine
Schools of Medicine
Chapel Hill
United States
Zip Code
He, Lihua; Aleksandrov, Andrei A; An, Jianli et al. (2015) Restoration of NBD1 thermal stability is necessary and sufficient to correct ?F508 CFTR folding and assembly. J Mol Biol 427:106-20
Roy, Michelle G; Livraghi-Butrico, Alessandra; Fletcher, Ashley A et al. (2014) Muc5b is required for airway defence. Nature 505:412-6
Henderson, Ashley G; Ehre, Camille; Button, Brian et al. (2014) Cystic fibrosis airway secretions exhibit mucin hyperconcentration and increased osmotic pressure. J Clin Invest 124:3047-60
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
Donnelley, Martin; Morgan, Kaye S; Siu, Karen K W et al. (2014) Non-invasive airway health assessment: synchrotron imaging reveals effects of rehydrating treatments on mucociliary transit in-vivo. Sci Rep 4:3689
Cholon, Deborah M; Quinney, Nancy L; Fulcher, M Leslie et al. (2014) Potentiator ivacaftor abrogates pharmacological correction of ?F508 CFTR in cystic fibrosis. Sci Transl Med 6:246ra96
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
Guo, Xueliang; Zheng, Shuo; Dang, Hong et al. (2014) Genome reference and sequence variation in the large repetitive central exon of human MUC5AC. Am J Respir Cell Mol Biol 50:223-32
Yang, Zhengrong; Wang, Chi; Zhou, Qingxian et al. (2014) Membrane protein stability can be compromised by detergent interactions with the extramembranous soluble domains. Protein Sci 23:769-89
Hill, David B; Vasquez, Paula A; Mellnik, John et al. (2014) A biophysical basis for mucus solids concentration as a candidate biomarker for airways disease. PLoS One 9:e87681

Showing the most recent 10 out of 12 publications