The PK/PD Core will provide 1) pharmacokinetic (PK) measurements of drug concentrations over time in airway surface liquid (ASL) from all three projects and 2) in-vivo pharmacodynamic (PD) measurements of mucociliary and cough clearance (MCC/CC) for the animal and human projects (Projects II and 111). 1. Pharmacokinetics. The pharmacological activities of drugs that affect mucus hydration are a reflection of their concentrations on airway surfaces. Measuring airway drug concentrations in human subjects is difficult using traditional methods. Bronchoscopic lavages suffer from variable dilutions and uncertainties about site sampled, and sputum likely reflects an abnormal secretion that originates primarily from large airway surfaces. Accordingly, we will develop mass spectrometric methods to accurately measure ASL concentrations of drugs, drug metabolites, and markers of ASL dilution that can be applied both to non-invasive airway samples such as exhaled breath condensate (EBC) and to other ASL samples obtained from all three projects. 2. Pharmacodynamics. Quantifying the response of mucociliary function to treatments targeted for chronic obstructive airways disease requires accurate, sensitive in-vivo measurements of MCC/CC for both animal and human models. Accordingly we will: a. Measure mucociliary clearance in mice by tracking tracheal velocities of fluorescently labeled beads for baseline and drug interventions that parallel those in the clinical projects. b. Measure MCC/CC in human subjects using techniques that standardize radiotracer deposition. Both baseline MCC/CC and the effects of mucolytic treatments will be assessed as described in Project 111. Measures of airways obstruction, ciliary dependent clearance (MCC), cough-dependent clearance (CC), and novel endpoints to describe heterogeneity of clearance will be made available to Project investigators. c. Engineer and produce novel particles of controlled size and shape for deposition on airway surfaces that 1) accurately track the movement of mucus from the lung and 2) permit multi-modal imaging (e.g. single photon emission computed tomography, positron emission tomography [PET], or MRI) to better delineate the degree and site of MCC abnormalities within the lungs of patients when combined with diagnostic imaging of lung structure (CT and MRI) and inflammation (PET).

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Special Emphasis Panel (ZHL1-CSR-Q)
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University of North Carolina Chapel Hill
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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 :

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