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CF airway smooth muscle transcriptome reveals a role for PYK2
Daniel P. Cook, … , Kin Fai Au, David A. Stoltz
Daniel P. Cook, … , Kin Fai Au, David A. Stoltz
Published September 7, 2017
Citation Information: JCI Insight. 2017;2(17):e95332. https://doi.org/10.1172/jci.insight.95332.
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Research Article Pulmonology

CF airway smooth muscle transcriptome reveals a role for PYK2

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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.

Authors

Daniel P. Cook, Ryan J. Adam, Keyan Zarei, Benjamin Deonovic, Mallory R. Stroik, Nicholas D. Gansemer, David K. Meyerholz, Kin Fai Au, David A. Stoltz

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Figure 1

Loss of CFTR leads to alterations in the airway smooth muscle transcriptome.

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Loss of CFTR leads to alterations in the airway smooth muscle transcript...
(A) Volcano plot showing differentially expressed genes due to CFTR loss in airway smooth muscle. The negative log10-transformed Q values are plotted against the average log2 fold changes in gene expression. Data for genes that were not classified as differentially expressed are plotted in gray. Data for genes that are differentially expressed due to CFTR loss (Q < 0.05) with an absolute log2 fold change of less than or equal to 1 are denoted by blue symbols and those with an absolute log2 fold change of greater than or equal to 1 are denoted by orange symbols. (B) Summary of gene changes in airway smooth muscle due to CFTR loss. (C) Gene set enrichment analysis for genes that were classified as upregulated or downregulated due to CFTR loss in airway smooth muscle. Data derived from MetaCore enrichment are represented in green, and data derived from Ingenuity Pathway Analysis (IPA) are represented in purple. Both databases were used to generate a list of the top 8 dysregulated pathways represented by the CFTR−/− airway smooth muscle signature. Dashed lines represent threshold cutoff for significance for each database. (D) A functionally grouped network of enriched categories was generated for targets altered due to CFTR loss in airway smooth muscle using gene ontology terms as nodes; these terms were linked using ClueGO analysis.

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