MicroRNA-145 Antagonism Reverses TGF-β Inhibition of F508del CFTR Correction in Airway Epithelia
| Autor: | Gang Liu, Marina Mazur, Namasivayam Ambalavanan, William T. Gerthoffer, Peng Li, William T. Harris, Tomasz Szul, Farruk M. Lutful Kabir, Brian Halloran, George M. Solomon, Steven M. Rowe, Charitharth Vivek Lal |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Critical Care and Intensive Care Medicine Cystic fibrosis 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Transforming Growth Factor beta microRNA F508del cftr medicine Humans Messenger RNA business.industry Lumacaftor Original Articles respiratory system medicine.disease respiratory tract diseases MicroRNAs 030104 developmental biology 030228 respiratory system chemistry Transforming Growth Factors Cancer research Antagonism business Airway Transforming growth factor |
| Zdroj: | American Journal of Respiratory and Critical Care Medicine. 197:632-643 |
| ISSN: | 1535-4970 1073-449X |
| Popis: | Rationale: MicroRNAs (miRNAs) destabilize mRNA transcripts and inhibit protein translation. miR-145 is of particular interest in cystic fibrosis (CF) as it has a direct binding site in the 3′-untranslated region of CFTR (cystic fibrosis transmembrane conductance regulator) and is upregulated by the CF genetic modifier TGF (transforming growth factor)-β. Objectives: To demonstrate that miR-145 mediates TGF-β inhibition of CFTR synthesis and function in airway epithelia. Methods: Primary human CF (F508del homozygous) and non-CF airway epithelial cells were grown to terminal differentiation at the air–liquid interface on permeable supports. TGF-β (5 ng/ml), a miR-145 mimic (20 nM), and a miR-145 antagonist (20 nM) were used to manipulate CFTR function. In CF cells, lumacaftor (3 μM) and ivacaftor (10 μM) corrected mutant F508del CFTR. Quantification of CFTR mRNA, protein, and function was done by standard techniques. Measurements and Main Results: miR-145 is increased fourfold in CF BAL fluid compared with non-CF (P |
| Databáze: | OpenAIRE |
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