Major human airways diseases, including CORD and CF, exhibit obstruction of airway lumens with mucus. This tPPG is based on the premise that novel biophysical and biochemical hypotheses are required to adequately describe airway mucus transport in health, predict how and when the system fails in disease, and invent novel therapies to treat these ainways diseases. We hypothesize that effective and specific therapies will require dual therapeutic activities: 1) a mucus "hydrating" activity;and 2) a "mucolytic" activity, i.e., an agent that wil decrease mucus cohesion and/or adhesion. This tPPG application presents three Projects and five Cores designed to provide the scientific basis, biomarkers, and tests of novel therapies to treat muco-obstructive diseases. The Administrative Core (Core A) will oversee the fusion of physical and biological sciences that underpins our attack on this problem, key pre-clinical models for testing novel therapeutic strategies, and clinical trials to accomplish our overarching goals of: 1) testing in human subjects novel delivery devices and single/combination therapies focused on airway re-hydration;and 2) developing a novel mucolytic platform and testing inhibitors of mucin gene transcription. Thus, Core A will oversee three Projects: 1) "The Biophysics of Mucus Hydration and Adhesion/Cohesion" -Michael Rubenstein, Ph.D., P.I.;2) "Mucus Obstructed Mice for Biomarker and Drug Development" - Richard Boucher, M.D., P.I.;3) "Targeting Defective Mucus Clearance in COPD" - Scott Donaldson, M.D., P.I. Core A will oversee four Cores: 1) Core B (the Biostatistics and Data Management Core);2) Core C (the Mucus Core), which will provide state-of-the-art measurements of mucin concentration/biophysical properties;3) Core D [the Pharmacokinetics/Pharmacodynamics (PK/PD) Core], which will provide a range of PK/PD methodologies for testing activities of topical muco-active agents;and 4) Core E (the Compound/Combination Selection Core) - which will provide in vitro and animal model screens. In sum, the activities of the tPPG are integrated to provide the scientific bases to initiate clinical studies of novel delivery devices, to test combinations of hydrating agents, and to develop a new mucolytic drug for therapy of COPD.

Public Health Relevance

Our overarching hypothesis is that a relatively dehydrated mucus layer, reflecting either depletion of salt/water, and/or increased mucin secretion, or both, produces a failure of mucus transport, mucus adhesion, and an ensuing sequence that produces inflammation, bacterial infection, and airways remodeling in major human diseases, e.g., COPD and CF. This tPGG is designed develop novel therapies and devices for these diseases in both near-term and longer term time frames.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
3P01HL108808-02S1
Application #
8774753
Study Section
Special Emphasis Panel (ZHL1-CSR-Q (F1))
Program Officer
Banks-Schlegel, Susan P
Project Start
2012-06-15
Project End
2017-05-31
Budget Start
2013-12-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$41,786
Indirect Cost
$14,295
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
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
Liu, Kun; Lukach, Ariella; Sugikawa, Kouta et al. (2014) Copolymerization of metal nanoparticles: a route to colloidal plasmonic copolymers. Angew Chem Int Ed Engl 53:2648-53
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
Schwab, Ute; Abdullah, Lubna H; Perlmutt, Olivia S et al. (2014) Localization of Burkholderia cepacia complex bacteria in cystic fibrosis lungs and interactions with Pseudomonas aeruginosa in hypoxic mucus. Infect Immun 82:4729-45
Chhetri, Raghav K; Blackmon, Richard L; Wu, Wei-Chen et al. (2014) Probing biological nanotopology via diffusion of weakly constrained plasmonic nanorods with optical coherence tomography. Proc Natl Acad Sci U S A 111:E4289-97
Roy, Michelle G; Livraghi-Butrico, Alessandra; Fletcher, Ashley A et al. (2014) Muc5b is required for airway defence. Nature 505:412-6
Stukalin, Evgeny B; Cai, Li-Heng; Kumar, N Arun et al. (2013) Self-Healing of Unentangled Polymer Networks with Reversible Bonds. Macromolecules 46:
Button, Brian; Okada, Seiko F; Frederick, Charles Brandon et al. (2013) Mechanosensitive ATP release maintains proper mucus hydration of airways. Sci Signal 6:ra46

Showing the most recent 10 out of 11 publications