Patients with cystic fibrosis (CF) and chronic bronchitis, i.e. COPD, exhibit a significantly reduced mucus clearance. The overarching goal of this project is to test the hypothesis that reduced rates of mucociliary and cough clearance in these patients are related to mucus dehydration and the resulting increased adhesion of mucus to cells as well as increased mucus cohesion strength. Both CF and COPD subjects exhibit an increase in ainvay mucus concentration, reflecting: 1) reduced ainway surface solvent (salt/water), e.g., as observed with CFTR dysfunction;2) mucin hypersecretion, as observed with goblet cell hyperplasia;or 3) a combination of the two. Based on our recent theoretical and experimental data, we have developed a novel model, referred to as the """"""""two-gel"""""""" model, that suggests that in addition to a mucus gel, ain/vays exhibit a """"""""periciliary"""""""" layer (PCL), which is also a gel formed by tethered mucins (MUC1, MUC4, and MUC16). Efficient clearance requires hydration of the PCL that is sustained as long as its osmotic pressure is higher than that of the mucus gel layer. Importantly, the osmotic pressure of the mucus layer is largely determined by the concentration of the secreted mucins MUC5AC and MUC5B. To test our two-gel hypothesis, we have developed novel techniques to measure mucus osmotic pressure, adhesion/cohesion strength, viscosity, and elastic modulus and to determine the effect of these physical properties on mucus transport rate for both normal and CF cultures. We propose that reducing mucus concentration, cohesion strength, and mucus adhesion to epithelial cells will restore effective mucus clearance and thus benefit both CF and COPD patients. The novel approach to physical processes in airway surface layer will allow us to identify the optimal combination of rehydration and pharmacological agents to restore/accelerate the rate of mucus clearance. The identified agents that reduce the adhesion/cohesion strength and restore normal mucus clearance will be tested in mouse models of obstructive lung disease (Project II) and in COPD patients (Projects III).

Public Health Relevance

This project focus on the developments and validation of new physical models of airway surface layer and the role of mucus hydration, adhesion and cohesion in controlling mucus clearance. These new ideas lead to systematic developments of new drugs aimed at restoring and maintaining mucus clearance in patients with obstructive lung diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL108808-02
Application #
8490424
Study Section
Special Emphasis Panel (ZHL1-CSR-Q)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$352,418
Indirect Cost
$114,298
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Kesimer, Mehmet; Ford, Amina A; Ceppe, Agathe et al. (2017) Airway Mucin Concentration as a Marker of Chronic Bronchitis. N Engl J Med 377:911-922
Esther Jr, Charles R; Hill, David B; Button, Brian et al. (2017) Sialic acid-to-urea ratio as a measure of airway surface hydration. Am J Physiol Lung Cell Mol Physiol 312:L398-L404
Everaers, Ralf; Grosberg, Alexander Y; Rubinstein, Michael et al. (2017) Flory theory of randomly branched polymers. Soft Matter 13:1223-1234
Wagner, Caroline E; Turner, Bradley S; Rubinstein, Michael et al. (2017) A Rheological Study of the Association and Dynamics of MUC5AC Gels. Biomacromolecules 18:3654-3664
Ribeiro, Carla M P; Lubamba, Bob A (2017) Role of IRE1?/XBP-1 in Cystic Fibrosis Airway Inflammation. Int J Mol Sci 18:
Peters, Brandon L; Pike, Darin Q; Rubinstein, Michael et al. (2017) Polymers at Liquid/Vapor Interface. ACS Macro Lett 6:1191-1195
Livraghi-Butrico, Alessandra; Wilkinson, Kristen J; Volmer, Allison S et al. (2017) Lung disease phenotypes caused by over-expression of combinations of alpha, beta, and gamma subunits of the epithelial sodium channel in mouse airways. Am J Physiol Lung Cell Mol Physiol :ajplung003822017
Jacobson, David R; McIntosh, Dustin B; Stevens, Mark J et al. (2017) Single-stranded nucleic acid elasticity arises from internal electrostatic tension. Proc Natl Acad Sci U S A 114:5095-5100
Simon, Joseph R; Carroll, Nick J; Rubinstein, Michael et al. (2017) Programming molecular self-assembly of intrinsically disordered proteins containing sequences of low complexity. Nat Chem 9:509-515
Abdullah, Lubna H; Coakley, Raymond; Webster, Megan J et al. (2017) Mucin Production and Hydration Responses to Mucopurulent Materials in Normal vs. CF Airway Epithelia. Am J Respir Crit Care Med :

Showing the most recent 10 out of 69 publications