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.
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.
|Henderson, Ashley G; Ehre, Camille; Button, Brian et al. (2014) Cystic fibrosis airway secretions exhibit mucin hyperconcentration and increased osmotic pressure. J Clin Invest 124:3047-60|
|Esther Jr, Charles R; Boucher, Richard C; Johnson, M Ross et al. (2014) Airway drug pharmacokinetics via analysis of exhaled breath condensate. Pulm Pharmacol Ther 27:76-82|
|Donnelley, Martin; Morgan, Kaye S; Siu, Karen K W et al. (2014) Non-invasive airway health assessment: synchrotron imaging reveals effects of rehydrating treatments on mucociliary transit in-vivo. Sci Rep 4:3689|
|Liu, Kun; Lukach, Ariella; Sugikawa, Kouta et al. (2014) Copolymerization of metal nanoparticles: a route to colloidal plasmonic copolymers. Angew Chem Int Ed Engl 53:2648-53|
|Hill, David B; Vasquez, Paula A; Mellnik, John et al. (2014) A biophysical basis for mucus solids concentration as a candidate biomarker for airways disease. PLoS One 9:e87681|
|Schwab, Ute; Abdullah, Lubna H; Perlmutt, Olivia S et al. (2014) Localization of Burkholderia cepacia complex bacteria in cystic fibrosis lungs and interactions with Pseudomonas aeruginosa in hypoxic mucus. Infect Immun 82:4729-45|
|Chhetri, Raghav K; Blackmon, Richard L; Wu, Wei-Chen et al. (2014) Probing biological nanotopology via diffusion of weakly constrained plasmonic nanorods with optical coherence tomography. Proc Natl Acad Sci U S A 111:E4289-97|
|Roy, Michelle G; Livraghi-Butrico, Alessandra; Fletcher, Ashley A et al. (2014) Muc5b is required for airway defence. Nature 505:412-6|
|Stukalin, Evgeny B; Cai, Li-Heng; Kumar, N Arun et al. (2013) Self-Healing of Unentangled Polymer Networks with Reversible Bonds. Macromolecules 46:|
|Button, Brian; Okada, Seiko F; Frederick, Charles Brandon et al. (2013) Mechanosensitive ATP release maintains proper mucus hydration of airways. Sci Signal 6:ra46|
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