{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T10:57:02Z","timestamp":1766401022464,"version":"build-2065373602"},"reference-count":61,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T00:00:00Z","timestamp":1638835200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["1048910","Practitioner Fellowship (S.M.S.)"],"award-info":[{"award-number":["1048910","Practitioner Fellowship (S.M.S.)"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Centre for Cell Therapy and Regenerative Medicine","award":["PhD Top-Up Scholarship"],"award-info":[{"award-number":["PhD Top-Up Scholarship"]}]},{"name":"Asthma Foundation WA","award":["Fiona Staniforth PhD Top-Up Scholarship"],"award-info":[{"award-number":["Fiona Staniforth PhD Top-Up Scholarship"]}]},{"name":"Rothwell Family Fellow","award":["Rothwell Family Fellow (A.K.)"],"award-info":[{"award-number":["Rothwell Family Fellow (A.K.)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>The airway epithelium of children with wheeze is characterized by defective repair that contributes to disease pathobiology. Dysregulation of developmental processes controlled by Notch has been identified in chronic asthma. However, its role in airway epithelial cells of young children with wheeze, particularly during repair, is yet to be determined. We hypothesized that Notch is dysregulated in primary airway epithelial cells (pAEC) of children with wheeze contributing to defective repair. This study investigated transcriptional and protein expression and function of Notch in pAEC isolated from children with and without wheeze. Primary AEC of children with and without wheeze were found to express all known Notch receptors and ligands, although pAEC from children with wheeze expressed significantly lower NOTCH2 (10-fold, p = 0.004) and higher JAG1 (3.5-fold, p = 0.002) mRNA levels. These dysregulations were maintained in vitro and cultures from children with wheeze displayed altered kinetics of both NOTCH2 and JAG1 expression during repair. Following Notch signaling inhibition, pAEC from children without wheeze failed to repair (wound closure rate of 76.9 \u00b1 3.2%). Overexpression of NOTCH2 in pAEC from children with wheeze failed to rescue epithelial repair following wounding. This study illustrates the involvement of the Notch pathway in airway epithelial wound repair in health and disease, where its dysregulation may contribute to asthma development.<\/jats:p>","DOI":"10.3390\/jpm11121323","type":"journal-article","created":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T11:00:23Z","timestamp":1638874823000},"page":"1323","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Dysregulated Notch Signaling in the Airway Epithelium of Children with Wheeze"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8462-5865","authenticated-orcid":false,"given":"Thomas","family":"Iosifidis","sequence":"first","affiliation":[{"name":"Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA 6009, Australia"},{"name":"Centre for Cell Therapy and Regenerative Medicine, School of Medicine, The University of Western Australia, Nedlands, WA 6009, Australia"},{"name":"School of Population Health, Curtin University, Bentley, WA 6102, Australia"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4224-2839","authenticated-orcid":false,"given":"Erika N.","family":"Sutanto","sequence":"additional","affiliation":[{"name":"Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA 6009, Australia"},{"name":"School of Population Health, Curtin University, Bentley, WA 6102, Australia"}]},{"given":"Samuel T.","family":"Montgomery","sequence":"additional","affiliation":[{"name":"Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA 6009, Australia"}]},{"given":"Patricia","family":"Agudelo-Romero","sequence":"additional","affiliation":[{"name":"Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA 6009, Australia"},{"name":"School of Molecular Science, The University of Western Australia, Nedlands, WA 6009, Australia"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4241-2321","authenticated-orcid":false,"given":"Kevin","family":"Looi","sequence":"additional","affiliation":[{"name":"Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA 6009, Australia"},{"name":"School of Population Health, Curtin University, Bentley, WA 6102, Australia"}]},{"given":"Kak-Ming","family":"Ling","sequence":"additional","affiliation":[{"name":"Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA 6009, Australia"},{"name":"Division of Paediatrics, Medical School, The University of Western Australia, Nedlands, WA 6009, Australia"}]},{"given":"Nicole C.","family":"Shaw","sequence":"additional","affiliation":[{"name":"Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA 6009, Australia"},{"name":"Division of Paediatrics, Medical School, The University of Western Australia, Nedlands, WA 6009, Australia"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9381-326X","authenticated-orcid":false,"given":"Luke W.","family":"Garratt","sequence":"additional","affiliation":[{"name":"Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA 6009, Australia"}]},{"given":"Jessica","family":"Hillas","sequence":"additional","affiliation":[{"name":"Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA 6009, Australia"}]},{"given":"Kelly M.","family":"Martinovich","sequence":"additional","affiliation":[{"name":"Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA 6009, Australia"},{"name":"Division of Paediatrics, Medical School, The University of Western Australia, Nedlands, WA 6009, Australia"}]},{"given":"Elizabeth","family":"Kicic-Starcevich","sequence":"additional","affiliation":[{"name":"Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA 6009, Australia"}]},{"given":"Shyan","family":"Vijayasekaran","sequence":"additional","affiliation":[{"name":"Division of Paediatrics, Medical School, The University of Western Australia, Nedlands, WA 6009, Australia"}]},{"given":"Francis J.","family":"Lannigan","sequence":"additional","affiliation":[{"name":"Division of Paediatrics, Medical School, The University of Western Australia, Nedlands, WA 6009, Australia"},{"name":"School of Medicine, Notre Dame University, Fremantle, WA 6160, Australia"}]},{"given":"Paul J.","family":"Rigby","sequence":"additional","affiliation":[{"name":"Centre of Microscopy, Characterisation and Analysis, The University of Western Australia, Nedlands, WA 6009, Australia"}]},{"given":"Darryl A.","family":"Knight","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW 2308, Australia"},{"name":"Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, Newcastle, NSW 2305, Australia"},{"name":"Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC V6H 3Z6, Canada"}]},{"given":"Stephen M.","family":"Stick","sequence":"additional","affiliation":[{"name":"Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA 6009, Australia"},{"name":"Centre for Cell Therapy and Regenerative Medicine, School of Medicine, The University of Western Australia, Nedlands, WA 6009, Australia"},{"name":"School of Molecular Science, The University of Western Australia, Nedlands, WA 6009, Australia"},{"name":"Department of Respiratory and Sleep Medicine, Perth Children\u2019s Hospital, Nedlands, WA 6009, Australia"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0008-9733","authenticated-orcid":false,"given":"Anthony","family":"Kicic","sequence":"additional","affiliation":[{"name":"Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA 6009, Australia"},{"name":"Centre for Cell Therapy and Regenerative Medicine, School of Medicine, The University of Western Australia, Nedlands, WA 6009, Australia"},{"name":"School of Population Health, Curtin University, Bentley, WA 6102, Australia"},{"name":"Department of Respiratory and Sleep Medicine, Perth Children\u2019s Hospital, Nedlands, WA 6009, Australia"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1007\/s00439-020-02151-5","article-title":"Comprehensive functional annotation of susceptibility variants associated with asthma","volume":"139","author":"Gautam","year":"2020","journal-title":"Hum. 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