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
Donoghue, Lauren J; Livraghi-Butrico, Alessandra; McFadden, Kathryn M et al. (2017) Identification of trans Protein QTL for Secreted Airway Mucins in Mice and a Causal Role for Bpifb1. Genetics 207:801-812
Sandefur, Conner I; Boucher, Richard C; Elston, Timothy C (2017) Mathematical model reveals role of nucleotide signaling in airway surface liquid homeostasis and its dysregulation in cystic fibrosis. Proc Natl Acad Sci U S A 114:E7272-E7281
Wang, Ling; Ariyarathna, Yamuna; Ming, Xin et al. (2017) A Novel Family of Small Molecules that Enhance the Intracellular Delivery and Pharmacological Effectiveness of Antisense and Splice Switching Oligonucleotides. ACS Chem Biol 12:1999-2007
Livraghi-Butrico, Alessandra; Grubb, Barbara R; Wilkinson, Kristen J et al. (2017) Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease. Mucosal Immunol 10:395-407
Sesma, Juliana I; Weitzer, Clarissa D; Livraghi-Butrico, Alessandra et al. (2016) UDP-glucose promotes neutrophil recruitment in the lung. Purinergic Signal 12:627-635
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
Dickey, Audrey S; Pineda, Victor V; Tsunemi, Taiji et al. (2016) PPAR-? is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically. Nat Med 22:37-45
Yu, Dongfang; Davis, Richard M; Aita, Megumi et al. (2016) Characterization of Rat Meibomian Gland Ion and Fluid Transport. Invest Ophthalmol Vis Sci 57:2328-43
Shobair, Mahmoud; Dagliyan, Onur; Kota, Pradeep et al. (2016) Gain-of-Function Mutation W493R in the Epithelial Sodium Channel Allosterically Reconfigures Intersubunit Coupling. J Biol Chem 291:3682-92
Kirby, Brett S; Schwarzbaum, Pablo J; Lazarowski, Eduardo R et al. (2015) Liberation of ATP secondary to hemolysis is not mutually exclusive of regulated export. Blood 125:1844-5

Showing the most recent 10 out of 41 publications