Your browser doesn't support javascript.
loading
A Neutralizing Aptamer to TGFBR2 and miR-145 Antagonism Rescue Cigarette Smoke- and TGF-ß-Mediated CFTR Expression.
Dutta, Rajib K; Chinnapaiyan, Srinivasan; Rasmussen, Lawrence; Raju, S Vamsee; Unwalla, Hoshang J.
Affiliation
  • Dutta RK; Department of Immunology and Nanomedicine, Institute of Neuroimmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA.
  • Chinnapaiyan S; Department of Immunology and Nanomedicine, Institute of Neuroimmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA.
  • Rasmussen L; Division of Pulmonary, Allergy, and Critical Care Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.
  • Raju SV; Division of Pulmonary, Allergy, and Critical Care Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.
  • Unwalla HJ; Department of Immunology and Nanomedicine, Institute of Neuroimmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA. Electronic address: hunwalla@fiu.edu.
Mol Ther ; 27(2): 442-455, 2019 02 06.
Article in En | MEDLINE | ID: mdl-30595527
Transforming growth factor ß (TGF-ß), signaling induced by cigarette smoke (CS), plays an important role in the progression of airway diseases, like chronic bronchitis associated with chronic obstructive pulmonary disease (COPD), and in smokers. Chronic bronchitis is characterized by reduced mucociliary clearance (MCC). Cystic fibrosis transmembrane conductance regulator (CFTR) plays an important role in normal MCC. TGF-ß and CS (via TGF-ß) promote acquired CFTR dysfunction by suppressing CFTR biogenesis and function. Understanding the mechanism by which CS promotes CFTR dysfunction can identify therapeutic leads to reverse CFTR suppression and rescue MCC. TGF-ß alters the microRNAome of primary human bronchial epithelium. TGF-ß and CS upregulate miR-145-5p expression to suppress CFTR and the CFTR modifier, SLC26A9. miR-145-5p upregulation with a concomitant CFTR and SLC26A9 suppression was validated in CS-exposed mouse models. While miR-145-5p antagonism rescued the effects of TGF-ß in bronchial epithelial cells following transfection, an aptamer to block TGF-ß signaling rescues CS- and TGF-ß-mediated suppression of CFTR biogenesis and function in the absence of any transfection reagent. These results demonstrate that miR-145-5p plays a significant role in acquired CFTR dysfunction by CS, and they validate a clinically feasible strategy for delivery by inhalation to locally modulate TGF-ß signaling in the airway and rescue CFTR biogenesis and function.
Subject(s)
Key words

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Smoking / Transforming Growth Factor beta / Cystic Fibrosis Transmembrane Conductance Regulator / Pulmonary Disease, Chronic Obstructive / MicroRNAs / Receptor, Transforming Growth Factor-beta Type II Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Mol Ther Year: 2019 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Smoking / Transforming Growth Factor beta / Cystic Fibrosis Transmembrane Conductance Regulator / Pulmonary Disease, Chronic Obstructive / MicroRNAs / Receptor, Transforming Growth Factor-beta Type II Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Mol Ther Year: 2019 Document type: Article