Mucus obstruction is a key pathogenic step in many major human ainways diseases, including COPD and CF. As part of the drug discovery process, it is extremely valuable to have a small animal model that will accelerate the transition from in vitro studies of target identification/validation to eariy proof-of-concept studies in humans. The (3ENaC mouse has been engineered to exhibit many of the features of muco-obstructive human airways diseases, expressing a disease-initiating transgene (PENaC) that drives ainA/ay surface dehydration. The ainways dehydration of the PENaC mouse triggers a sequence of intraluminal airways mucus plaque/plug formation, airways inflammation with macrophage activation, ain/vays remodeling, bacterial infection, and emphysema. In Project II, we propose to contribute to the tPPG goals and needs for drug development as follows: 1) test in vivo the novel biophysical/biochemical formulation of a "two-gel" mucus clearance system, focusing on relationships between the rate of delivery of hypertonic saline (HS) and mucus clearance responses;2) develop novel measures of mucus properties that will serve as validated biomarkers to predict the magnitude of the "ain/vay mucus burden", i.e., our therapeutic target, utilizing PENaC mouse lines of differing ainways Na+ transport/ainway surface dehydration;3) test the hypothesis that secreted mucins (MUC5AC, MUCSB) are "therapeutic targets" with favorable risk:benefit ratios by genetic studies of MUC5AC and MUCSB -/- crosses with PENaC mice and pharmacologic (novel ketolides/macrolides) approaches;and 4) test the hypothesis that bacterial infection of mucus-obstructed ainways can be prevented or reversed by hydration/mucolytic therapies. Thus, Project II should provide important in vivo data as to the validity of our novel "two-gel" model of mucus transport, identify biomarkers for pharmacodynamic studies of mucus modification to speed drug development in both animals and the clinic, and assist Core A to identify relevant targets and novel therapies of muco-obstructive lung disease.

Public Health Relevance

Muco-obstructive airways diseases affect >15 M Americans, both COPD and CF subjects. Drug development has been slow, due to lack of theoretical understanding of mucus clearance in health and how it fails in disease, and lack of a small animal model for the drug development process. Project II will test in such a model important concepts, and identify biomarkers, and targets, and indications for such therapy. Project II has the potential to greatly improve the treatment of patients with this unmet medical need.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL108808-01A1
Application #
8292399
Study Section
Special Emphasis Panel (ZHL1-CSR-Q (F1))
Project Start
Project End
Budget Start
2012-06-15
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$471,159
Indirect Cost
$152,808
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