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      Phenotyping ciliary dynamics and coordination in response to CFTR-modulators in Cystic Fibrosis respiratory epithelial cells

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          Abstract

          Personalized approaches for systematically assessing ciliary beat dynamics and for drug testing would improve the challenging task of diagnosing and treating respiratory disorders. In this pilot study, we show how multiscale differential dynamic microscopy (multi-DDM) can be used to characterize collective ciliary beating in a non-biased automated manner. We use multi-DDM to assess the efficacy of different CFTR-modulating drugs in human airway epithelial cells derived from subjects with cystic fibrosis (ΔF508/ΔF508 and ∆F508/-) based on ciliary beat frequency and coordination. Similar to clinical observations, drug efficacy is variable across donors, even within the same genotype. We show how our assay can quantitatively identify the most efficient drugs for restoring ciliary beating for each individual donor. Multi-DDM provides insight into ciliary beating responses following treatment with drugs, and has application in the broader context of respiratory disease and for drug screening.

          Abstract

          Personalized approaches to diagnosis and treatment monitoring could improve the management of cystic fibrosis patients. Here the authors show that multiscale differential dynamic microscopy can assess changes in cilia beating dynamics and coordination in patient-derived airway epithelial cells, in response to different CFTR-modulating drugs, in a patient-specific manner.

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          Most cited references 26

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          Ciliopathies.

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            Airway mucus function and dysfunction.

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              Cystic fibrosis.

              Cystic fibrosis is the most common lethal genetic disease in white populations. The outlook for patients with the disease has improved steadily over many years, largely as a result of earlier diagnosis, more aggressive therapy, and provision of care in specialised centres. Researchers now have a more complete understanding of the molecular-biological defect that underlies cystic fibrosis, which is leading to new approaches to treatment. One of these treatments, hypertonic saline, is already in use, whereas others are in advanced stages of development. We review clinical care for cystic fibrosis and discuss recent advances in the understanding of its pathogenesis, implementation of screening of neonates, and development of therapies aimed at treating the basic defect.
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                Author and article information

                Contributors
                BratcherP@NJHealth.org
                pc245@cam.ac.uk
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                16 April 2019
                16 April 2019
                2019
                : 10
                Affiliations
                [1 ]ISNI 0000000121885934, GRID grid.5335.0, Biological and Soft Systems Sector, Cavendish Laboratory, , University of Cambridge, ; Cambridge, CB3 0HE UK
                [2 ]ISNI 0000000419368710, GRID grid.47100.32, Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, , Yale School of Medicine, ; New Haven, CT 06510 USA
                [3 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Institute of Clinical Sciences, , Imperial College London, ; London, SW7 2AZ UK
                [4 ]ISNI 0000000122478951, GRID grid.14105.31, MRC London Institute of Medical Sciences, ; London, W12 0NN UK
                [5 ]ISNI 0000 0004 0396 0728, GRID grid.240341.0, Division of Cell Biology, Department of Pediatrics, , National Jewish Health, ; Denver, CO 80206 USA
                Article
                9798
                10.1038/s41467-019-09798-3
                6467870
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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