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.
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.
|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|
|Muhlebach, Marianne S; Hatch, Joseph E; Einarsson, Gisli G et al. (2018) Anaerobic bacteria cultured from cystic fibrosis airways correlate to milder disease: a multisite study. Eur Respir J 52:|
|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|
|Bennett, William D; Zeman, Kirby L; Laube, Beth L et al. (2018) Homogeneity of Aerosol Deposition and Mucociliary Clearance are Improved Following Ivacaftor Treatment in Cystic Fibrosis. J Aerosol Med Pulm Drug Deliv 31:204-211|
|Ge, Ting; Grest, Gary S; Rubinstein, Michael (2018) Nanorheology of Entangled Polymer Melts. Phys Rev Lett 120:057801|
|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|
|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|
|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|
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