Cystic Fibrosis Pulmonary Research and Treatment Center

Chapel Hill, NC, United States

Cystic Fibrosis Pulmonary Research and Treatment Center

Chapel Hill, NC, United States
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Austin-Tse C.,Massachusetts General Hospital | Austin-Tse C.,Harvard University | Halbritter J.,Harvard University | Zariwala M.A.,University of North Carolina at Chapel Hill | And 42 more authors.
American Journal of Human Genetics | Year: 2013

Primary ciliary dyskinesia (PCD) is caused when defects of motile cilia lead to chronic airway infections, male infertility, and situs abnormalities. Multiple causative PCD mutations account for only 65% of cases, suggesting that many genes essential for cilia function remain to be discovered. By using zebrafish morpholino knockdown of PCD candidate genes as an in vivo screening platform, we identified c21orf59, ccdc65, and c15orf26 as critical for cilia motility. c21orf59 and c15orf26 knockdown in zebrafish and planaria blocked outer dynein arm assembly, and ccdc65 knockdown altered cilia beat pattern. Biochemical analysis in Chlamydomonas revealed that the C21orf59 ortholog FBB18 is a flagellar matrix protein that accumulates specifically when cilia motility is impaired. The Chlamydomonas ida6 mutant identifies CCDC65/FAP250 as an essential component of the nexin-dynein regulatory complex. Analysis of 295 individuals with PCD identified recessive truncating mutations of C21orf59 in four families and CCDC65 in two families. Similar to findings in zebrafish and planaria, mutations in C21orf59 caused loss of both outer and inner dynein arm components. Our results characterize two genes associated with PCD-causing mutations and elucidate two distinct mechanisms critical for motile cilia function: dynein arm assembly for C21orf59 and assembly of the nexin-dynein regulatory complex for CCDC65. © 2013 The American Society of Human Genetics. All rights reserved.


PubMed | Cystic Fibrosis Pulmonary Research and Treatment Center and University of North Carolina
Type: Journal Article | Journal: Journal of pharmacovigilance | Year: 2014

Asthma, Chronic Obstructive Pulmonary Disease (COPD) and Cystic Fibrosis (CF) are all pulmonary diseases which are characterized by chronic inflammation and an increase in mucus production. Excess mucus in the airways correlates with pathophysiology such as a decline in lung function and prolonged bacterial infections. New drugs to treat these chronic respiratory diseases are currently being developed and include both inhaled and orally administered compounds. Whilst oral drugs may be easier to administer, they are more prone to side-effects due to higher bioavailability. Inhaled compounds may show reduced bioavailability, but face their own unique challenges. For example, thick mucus in the respiratory tracts of asthma, CF and COPD patients can act as a physical barrier that impedes drug delivery. Mucus also contains a high number of enzymes and proteases that may degrade compounds before they reach their site of action. Furthermore, some classes of drugs are rapidly absorbed across the respiratory epithelia into systemic circulation, which may limit their duration of action and/or cause off-target effects. This review discusses some of the different treatment options that are currently available and the considerations that need to be taken into account to produce new therapies for the treatment of chronic respiratory diseases.


Caldwell R.A.,Cystic Fibrosis Pulmonary Research and Treatment Center | Grove D.E.,University of North Carolina at Chapel Hill | Houck S.A.,University of North Carolina at Chapel Hill | Cyr D.M.,Cystic Fibrosis Pulmonary Research and Treatment Center | Cyr D.M.,University of North Carolina at Chapel Hill
American Journal of Physiology - Lung Cellular and Molecular Physiology | Year: 2011

Cystic fibrosis (CF) is a lethal recessive genetic disease caused by mutations in the CFTR gene. The gene product is a PKA-regulated anion channel that is important for fluid and electrolyte transport in the epithelia of lung, gut, and ducts of the pancreas and sweat glands. The most common CFTR mutation, δF508, causes a severe, but correctable, folding defect and gating abnormality, resulting in negligible CFTR function and disease. There are also a large number of rare CF-related mutations where disease is caused by CFTR misfolding. Yet the extent to which defective biogenesis of these CFTR mutants can be corrected is not clear. CFTRV232D is one such mutant that exhibits defective folding and trafficking. CFTRδF508 misfolding is difficult to correct, but defective biogenesis of CFTRV232D is corrected to near wildtype levels by small-molecule folding correctors in development as CF therapeutics. To determine if CFTRV232D protein is competent as a Cl- channel, we utilized single-channel recordings from transfected human embryonic kidney (HEK-293) cells. After PKA stimulation, CFTRV232D channels were detected in patches with a unitary Cl- conductance indistinguishable from that of CFTR. Yet the frequency of detecting CFTRV232D channels was reduced to ~20% of patches compared with 60% for CFTR. The folding corrector Corr-4a increased the CFTRV232D channel detection rate and activity to levels similar to CFTR. CFTRV232D-corrected channels were inhibited with CFTRinh-172 and stimulated fourfold by the CFTR channel potentiator VRT-532. These data suggest that CF patients with rare mutations that cause CFTR misfolding, such as CFTRV232D, may benefit from treatment with folding correctors and channel potentiators in development to restore CFTRδF508 function. © 2011 the American Physiological Society.


Hobbs C.A.,Cystic Fibrosis Pulmonary Research and Treatment Center | Da Tan C.,Cystic Fibrosis Pulmonary Research and Treatment Center | Tarran R.,Cystic Fibrosis Pulmonary Research and Treatment Center | Tarran R.,University of North Carolina at Chapel Hill
Journal of Physiology | Year: 2013

Airway epithelia absorb Na+ through the epithelial Na+ channel (ENaC) and secrete Cl- through the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. This balance maintains sufficient airway surface liquid hydration to permit efficient mucus clearance, which is needed to maintain sterility of the lung. Cystic fibrosis (CF) is a common autosomal recessive inherited disease caused by mutations in the CFTR gene that lead to the reduction or elimination of the CFTR protein. CF is a multi-organ disease that affects epithelia lining the intestines, lungs, pancreas, sweat ducts and vas deferens, among others. CF lungs are characterized by viscous, dehydrated mucus, persistent neutrophilia and chronic infections. ENaC is negatively regulated by CFTR and, in patients with CF, the absence of CFTR results in a double hit of reduced Cl-/HCO3- and H2O secretion as well as ENaC hyperactivity and increased Na+ and H2O absorption. Together, these effects are hypothesized to trigger mucus dehydration, resulting in a failure to clear mucus. Rehydrating CF mucus has become a recent clinical focus and yields important end-points for clinical trials. However, while ENaC hyperactivity in CF airways has been detected in vivo and in vitro, recent data have brought the role of ENaC in CF lung disease pathogenesis into question. This review will focus on our current understanding of the contribution of ENaC to CF pathogenesis. © 2013 The Authors. The Journal of Physiology © 2013 The Physiological Society.

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