Ineffective mucociliary clearance (MCC) is a common pathophysiologic process contributing to chronic rhinosinusitis (CRS) - a highly prevalent disease with substantial morbidity. Evidence from our laboratory has demonstrated that brief exposures to lipopolysaccharide (LPS) from gram-negative bacteria lead to dysfunctional MCC by decreasing anion transport through CFTR apical Cl- channels in humans and other mammalian species. CFTR inhibition in this setting is caused by TLR4-mediated generation of reactive oxygen species (ROS), but independent of NFkB-derived inflammation. Furthermore, our group has confirmed the presence of acquired CFTR dysfunction in human sinuses, and has demonstrated that CFTR potentiators can stimulate Cl- secretion when partial CFTR dysfunction is present in multiple in vitro and preclinical models. Our central hypotheses are that LPS-induced acquired CFTR deficiency, 1) contributes substantially to the pathogenesis of CRS, and 2) can be treated with Ivacaftor, a CFTR potentiator developed for CF therapy.
Specific Aim 1 will investigate the mechanistic basis of LPS-mediated CFTR dysfunction in sinonasal epithelium by 1) examining the oxidant-dependent inhibition of CFTR via AMP-dependent kinase (an inhibitor of PKA-dependent phosphorylation of the CFTR regulatory domain), 2) assessing the impact of ROS (superoxide, hydrogen peroxide) on CFTR function (patch clamp analysis) and structure (mass spectrometry), and 3) measuring the effects of longer exposures to LPS on CFTR expression, maturational processing, and recycling.
Aim 2 will identify the efficiency of Ivacaftor in improving CFTR function in a pre-clinical rabbit model of acquired CFTR deficiency by 1) developing normative data for LPS-exposed rabbit maxillary sinus CFTR dysfunction, 2) assessing the effects of Ivacaftor on CFTR-related endpoints, and 3) evaluating Ivacaftor as therapy for Pseudomonas aeruginosa rabbit maxillary sinusitis.
Aim 3 will conduct a clinical study using Ivacaftor in CRS patients by 1) correlating the novel ?endoscopically-directed sinus potential difference? assay to validated measures of CRS disease severity and 2) performing a pilot clinical trial using Ivacaftor for CRS patients with refractory gram-negative bacterial CRS. The current proposal will help clarify mechanisms responsible for sinusitis pathogenesis, but also translates our laboratory findings to human subjects by providing a clinical trial using Ivacaftor for therapy of sinusitis. We believe our application will answer fundamental questions regarding pathomechanisms underlying CRS and establish the foundation for a new therapeutic approach to a serious and debilitating chronic disease.

Public Health Relevance

Evidence from our laboratory has demonstrated that brief exposures to lipopolysaccharide ? a component of gram-negative bacterial cell walls - lead to dysfunctional mucus clearance by decreasing transport of chloride (Cl-) ions through the cystic fibrosis transmembrane conductance regulator (CFTR) present on the surface of airway cells. Furthermore, our group has confirmed the existence of acquired CFTR dysfunction in the sinuses of human subjects with chronic rhinosinusitis, and that the drug Ivacaftor (developed for therapy of cystic fibrosis) overcomes acquired Cl- secretory defects present in multiple in vitro and in vivo model systems. The current proposal will help clarify mechanisms responsible for sinusitis pathogenesis, and also translate our laboratory findings to human subjects by providing a clinical trial using Ivacaftor for therapy of non-CF sinusitis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL133006-01
Application #
9156126
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Sheridan, John T
Project Start
2016-08-01
Project End
2021-05-31
Budget Start
2016-08-01
Budget End
2017-05-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Cho, Do-Yeon; Lim, Dong-Jin; Mackey, Calvin et al. (2018) l-Methionine anti-biofilm activity against Pseudomonas aeruginosa is enhanced by the cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor. Int Forum Allergy Rhinol 8:577-583
Cho, Do-Yeon; Lim, Dong-Jin; Mackey, Calvin et al. (2018) Preclinical therapeutic efficacy of the ciprofloxacin-eluting sinus stent for Pseudomonas aeruginosa sinusitis. Int Forum Allergy Rhinol 8:482-489
Tipirneni, Kiranya E; Zhang, Shaoyan; Cho, Do-Yeon et al. (2018) Submucosal gland mucus strand velocity is decreased in chronic rhinosinusitis. Int Forum Allergy Rhinol 8:509-512
Tipirneni, Kiranya E; Woodworth, Bradford A (2017) Medical and Surgical Advancements in the Management of Cystic Fibrosis Chronic Rhinosinusitis. Curr Otorhinolaryngol Rep 5:24-34
Cho, Do-Yeon; Mackey, Calvin; Van Der Pol, William J et al. (2017) Sinus Microanatomy and Microbiota in a Rabbit Model of Rhinosinusitis. Front Cell Infect Microbiol 7:540
Cho, Do-Yeon; Hoffman, Kyle J; Gill, Gobind S et al. (2017) Protective and antifungal properties of Nanodisk-Amphotericin B over commercially available Amphotericin B. World J Otorhinolaryngol Head Neck Surg 3:2-8
Fong, Stephanie A; Drilling, Amanda; Morales, Sandra et al. (2017) Activity of Bacteriophages in Removing Biofilms of Pseudomonas aeruginosa Isolates from Chronic Rhinosinusitis Patients. Front Cell Infect Microbiol 7:418
Grayson, Jessica; Tipirneni, Kiranya E; Skinner, Daniel F et al. (2017) Sinus hypoplasia in the cystic fibrosis rat resolves in the absence of chronic infection. Int Forum Allergy Rhinol 7:904-909
Tipirneni, Kiranya E; Grayson, Jessica W; Zhang, Shaoyan et al. (2017) Assessment of acquired mucociliary clearance defects using micro-optical coherence tomography. Int Forum Allergy Rhinol 7:920-925
Tipirneni, Kiranya E; Cho, Do-Yeon; Skinner, Daniel F et al. (2017) Characterization of primary rat nasal epithelial cultures in CFTR knockout rats as a model for CF sinus disease. Laryngoscope 127:E384-E391

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