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).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL108808-03
Application #
8686934
Study Section
Special Emphasis Panel (ZHL1-CSR-Q)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
$361,356
Indirect Cost
$117,397
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Pandiyarajan, C K; Rubinstein, Michael; Genzer, Jan (2016) Surface-Anchored Poly(N-isopropylacrylamide) Orthogonal Gradient Networks. Macromolecules 49:5076-5083
Sesma, Juliana I; Weitzer, Clarissa D; Livraghi-Butrico, Alessandra et al. (2016) UDP-glucose promotes neutrophil recruitment in the lung. Purinergic Signal 12:627-635
Livraghi-Butrico, A; Grubb, B R; Wilkinson, K J et al. (2016) Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease. Mucosal Immunol :
Leuty, Gary M; Tsige, Mesfin; Grest, Gary S et al. (2016) Tension Amplification in Tethered Layers of Bottle-Brush Polymers. Macromolecules 49:1950-1960
Baeza, Guilhem P; Dessi, Claudia; Costanzo, Salvatore et al. (2016) Network dynamics in nanofilled polymers. Nat Commun 7:11368
Button, Brian; Anderson, Wayne H; Boucher, Richard C (2016) Mucus Hyperconcentration as a Unifying Aspect of the Chronic Bronchitic Phenotype. Ann Am Thorac Soc 13 Suppl 2:S156-62
Yu, Dongfang; Davis, Richard M; Aita, Megumi et al. (2016) Characterization of Rat Meibomian Gland Ion and Fluid Transport. Invest Ophthalmol Vis Sci 57:2328-43
Choueiri, Rachelle M; Galati, Elizabeth; Thérien-Aubin, Héloïse et al. (2016) Surface patterning of nanoparticles with polymer patches. Nature 538:79-83
Ramsey, Kathryn A; Rushton, Zachary L; Ehre, Camille (2016) Mucin Agarose Gel Electrophoresis: Western Blotting for High-molecular-weight Glycoproteins. J Vis Exp :
Bennett, William D; Henderson, Ashley G; Donaldson, Scott H (2016) Hydrator Therapies for Chronic Bronchitis. Lessons from Cystic Fibrosis. Ann Am Thorac Soc 13 Suppl 2:S186-90

Showing the most recent 10 out of 65 publications