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Short palate lung and nasal epithelial clone 1 (SPLUNC1) is an asthma gene modifier that inhibits Orai1 and SOCE via its C-terminal \u03b16 region. SPLUNC1 levels are diminished in asthma patient airways. Thus, we hypothesized that inhaled \u03b16 peptidomimetics could inhibit Orai1 and reduce airway inflammation in a murine asthma model. To evaluate \u03b16\u2013Orai1 interactions, we used fluorescent assays to measure Ca2+\u2009signaling, F\u00f6rster resonance energy transfer, fluorescent recovery after photobleaching, immunostaining, total internal reflection microscopy, and Western blotting. To test whether \u03b16 peptidomimetics inhibited SOCE and decreased inflammation in vivo, wild-type and SPLUNC1\u2212\/\u2212 mice were exposed to house dust mite (HDM) extract with or without \u03b16 peptide. We also performed nebulization, jet milling, and scanning electron microscopy to evaluate \u03b16 for inhalation. SPLUNC1\u2212\/\u2212 mice had an exaggerated response to HDM. In BAL-derived immune cells, Orai1 levels increased after HDM exposure in SPLUNC1\u2212\/\u2212 but not wild-type mice. Inhaled \u03b16 reduced Orai1 levels in mice regardless of genotype. In HDM-exposed mice, \u03b16 dose-dependently reduced eosinophilia and neutrophilia. In vitro, \u03b16 inhibited SOCE in multiple immune cell types, and \u03b16 could be nebulized or jet milled without loss of function. These data suggest that \u03b16 peptidomimetics may be a novel, effective antiinflammatory therapy for patients with asthma.<\/jats:p>","DOI":"10.1165\/rcmb.2020-0452oc","type":"journal-article","created":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T13:46:19Z","timestamp":1637588779000},"page":"271-282","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":26,"title":["A SPLUNC1 Peptidomimetic Inhibits Orai1 and Reduces Inflammation in a Murine Allergic Asthma Model"],"prefix":"10.1093","volume":"66","author":[{"given":"Joe A.","family":"Wrennall","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Physiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saira","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin N.","family":"Worthington","sequence":"additional","affiliation":[{"name":"Division of Pulmonology, Department of Pediatrics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongde","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra S.","family":"Goriounova","sequence":"additional","affiliation":[{"name":"Department of Pharmacology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis S.","family":"Voeller","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian E.","family":"Stewart","sequence":"additional","affiliation":[{"name":"Center for Engineered Systems, Research Triangle Institute International, Research Triangle Park, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arunava","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krzysztof","family":"Krajewski","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven L.","family":"Tilley","sequence":"additional","affiliation":[{"name":"Division of Pulmonology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J.","family":"Hickey","sequence":"additional","affiliation":[{"name":"Center for Engineered Systems, Research Triangle Institute International, Research Triangle Park, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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