Antisense Oligonucleotides Targeting Jagged 1 Reduce House Dust Mite–induced Goblet Cell Metaplasia in the Adult Murine Lung
| العنوان: | Antisense Oligonucleotides Targeting Jagged 1 Reduce House Dust Mite–induced Goblet Cell Metaplasia in the Adult Murine Lung |
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| المؤلفون: | Steven Kuntz, Brett P. Monia, Sagar S. Damle, Jeff Crosby, Guizhen Sun, Tamar R. Grossman, Christopher E. Hart, Michele Carrer, Chenguang Zhao |
| المصدر: | American Journal of Respiratory Cell and Molecular Biology. 63:46-56 |
| بيانات النشر: | American Thoracic Society, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Pulmonary and Respiratory Medicine, House dust mite, Goblet cell, JAG1, Lung, biology, Clinical Biochemistry, Notch signaling pathway, Cell Biology, respiratory system, biology.organism_classification, Mucus, medicine.anatomical_structure, Club cell, Metaplasia, medicine, Cancer research, medicine.symptom, Molecular Biology |
| الوصف: | Goblet cell metaplasia, excessive mucus production, and inadequate mucus clearance accompany and exacerbate multiple chronic respiratory disorders, such as asthma and chronic obstructive pulmonary disease. Notch signaling plays a central role in controlling the fate of multiple cell types in the lung, including goblet cells. In the present study, we explored the therapeutic potential of modulating the Notch pathway in the adult murine lung using chemically modified antisense oligonucleotides (ASOs). To this end, we designed and characterized ASOs targeting the Notch receptors Notch1, Notch2, and Notch3 and the Notch ligands Jag1 (Jagged 1) and Jag2 (Jagged 2). Pulmonary delivery of ASOs in healthy mice or mice exposed to house dust mite, a commonly used mouse model of asthma, resulted in a significant reduction of the respective mRNAs in the lung. Furthermore, ASO-mediated knockdown of Jag1 or Notch2 in the lungs of healthy adult mice led to the downregulation of the club cell marker Scgb1a1 and the concomitant upregulation of the ciliated cell marker FoxJ1 (forkhead box J1). Similarly, ASO-mediated knockdown of Jag1 or Notch2 in the house dust mite disease model led to reduced goblet cell metaplasia and decreased mucus production. Because goblet cell metaplasia and excessive mucus secretion are a common basis for many lung pathologies, we propose that ASO-mediated inhibition of JAG1 could provide a novel therapeutic path for the treatment of multiple chronic respiratory diseases. |
| تدمد: | 1535-4989 1044-1549 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::08cf6ec53a3352545b1aeff995632a1f https://doi.org/10.1165/rcmb.2019-0257oc |
| رقم الأكسشن: | edsair.doi...........08cf6ec53a3352545b1aeff995632a1f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15354989 10441549 |
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