Journal article
CF airway smooth muscle transcriptome reveals a role for PYK2
JCI insight, Vol.2(17), e95332
09/07/2017
DOI: 10.1172/jci.insight.95332
PMCID: PMC5621916
PMID: 28878137
Abstract
Abnormal airway smooth muscle function can contribute to cystic fibrosis (CF) airway disease. We previously found that airway smooth muscle from newborn CF pigs had increased basal tone, an increased bronchodilator response, and abnormal calcium handling. Since CF pigs lack airway infection and inflammation at birth, these findings suggest intrinsic airway smooth muscle dysfunction in CF. In this study, we tested the hypothesis that CFTR loss in airway smooth muscle would produce a distinct set of changes in the airway smooth muscle transcriptome that we could use to develop novel therapeutic targets. Total RNA sequencing of newborn wild-type and CF airway smooth muscle revealed changes in muscle contraction–related genes, ontologies, and pathways. Using connectivity mapping, we identified several small molecules that elicit transcriptional signatures opposite of CF airway smooth muscle, including NVP-TAE684, an inhibitor of proline-rich tyrosine kinase 2 (PYK2). In CF airway smooth muscle tissue, PYK2 phosphorylation was increased and PYK2 inhibition decreased smooth muscle contraction. In vivo NVP-TAE684 treatment of wild-type mice reduced methacholine-induced airway smooth muscle contraction. These findings suggest that studies in the newborn CF pig may provide an important approach to enhance our understanding of airway smooth muscle biology and for discovery of novel airway smooth muscle therapeutics for CF and other diseases of airway hyperreactivity.
Transcriptomic studies and connectivity mapping in CF pig airway smooth muscle identified PYK2 as a potential therapeutic target for airway smooth muscle dysfunction.
Details
- Title: Subtitle
- CF airway smooth muscle transcriptome reveals a role for PYK2
- Creators
- Daniel P Cook - Department of Internal MedicineRyan J Adam - Department of Biomedical Engineering, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAKeyan Zarei - Department of Biomedical Engineering, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USABenjamin Deonovic - Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, Iowa, USAMallory R Stroik - Department of Internal MedicineNicholas D Gansemer - Department of Internal MedicineDavid K Meyerholz - Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAKin Fai Au - Department of Internal MedicineDavid A Stoltz - Department of Internal Medicine
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.2(17), e95332
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/jci.insight.95332
- PMID
- 28878137
- PMCID
- PMC5621916
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Grant note
- HL051670 / NIH 117744 / NIH 12-0162 / ; T32 GM007337 / NIH T32 HL007638 / NIH S10 OD016316 / NIH WELSH15R0 / ; HL091842 / NIH
- Language
- English
- Date published
- 09/07/2017
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Pathology; Internal Medicine
- Record Identifier
- 9984025374802771
Metrics
22 Record Views