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
Abdullah, Lubna H; Coakley, Raymond; Webster, Megan J et al. (2018) Mucin Production and Hydration Responses to Mucopurulent Materials in Normal versus Cystic Fibrosis Airway Epithelia. Am J Respir Crit Care Med 197:481-491
Yu, Dongfang; Saini, Yogesh; Chen, Gang et al. (2018) Loss of ? Epithelial Sodium Channel Function in Meibomian Glands Produces Pseudohypoaldosteronism 1-Like Ocular Disease in Mice. Am J Pathol 188:95-110
Rowson-Hodel, A R; Wald, J H; Hatakeyama, J et al. (2018) Membrane Mucin Muc4 promotes blood cell association with tumor cells and mediates efficient metastasis in a mouse model of breast cancer. Oncogene 37:197-207
Terryah, Shawn T; Fellner, Robert C; Ahmad, Saira et al. (2018) Evaluation of a SPLUNC1-derived peptide for the treatment of cystic fibrosis lung disease. Am J Physiol Lung Cell Mol Physiol 314:L192-L205
Muhlebach, Marianne S; Zorn, Bryan T; Esther, Charles R et al. (2018) Initial acquisition and succession of the cystic fibrosis lung microbiome is associated with disease progression in infants and preschool children. PLoS Pathog 14:e1006798
Shobair, Mahmoud; Popov, Konstantin I; Dang, Yan L et al. (2018) Mapping allosteric linkage to channel gating by extracellular domains in the human epithelial sodium channel. J Biol Chem 293:3675-3684
Kota, Pradeep; Gentzsch, Martina; Dang, Yan L et al. (2018) The N terminus of ?-ENaC mediates ENaC cleavage and activation by furin. J Gen Physiol 150:1179-1187
Livraghi-Butrico, Alessandra; Wilkinson, Kristen J; Volmer, Allison S et al. (2018) Lung disease phenotypes caused by overexpression of combinations of ?-, ?-, and ?-subunits of the epithelial sodium channel in mouse airways. Am J Physiol Lung Cell Mol Physiol 314:L318-L331
Chen, Gang; Volmer, Allison S; Wilkinson, Kristen J et al. (2018) Role of Spdef in the Regulation of Muc5b Expression in the Airways of Naive and Mucoobstructed Mice. Am J Respir Cell Mol Biol 59:383-396
Livraghi-Butrico, A; Grubb, B R; Wilkinson, K J et al. (2017) Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease. Mucosal Immunol 10:829

Showing the most recent 10 out of 56 publications