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.
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|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 :|
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