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LSC - 2017 - Hippo-YAP/TAZ signaling is deranged in IPF

Wagner, Darcy LU ; Alsafadi, Hani LU ; Mutze, Kathrin; Costa, Rita; Stein, Marlene; Schiller, Herbert; Kaminski, Naftali and Koenigshoff, Melanie (2017) In European Respiratory Journal1988-01-01+01:00 50(Suppl. 61).
Abstract
Objective: Idiopathic pulmonary fibrosis (IPF) is a devastating disease with no cure and is characterized by deranged epithelial repair, myofibroblast activation, and excess deposition of extracellular matrix. Yes associated protein (YAP) and transcriptional co-regulator with PDZ-binding domain(TAZ), co-transcriptional activators of the Hippo pathway and proto-oncogenes, were recently found to be deranged in IPF. The cause of their dysregulation remain unknown. Hippo signaling regulates several endogenous progenitor cell functions through YAP/TAZ. We hypothesized that Hippo signaling is downregulated in IPF, resulting in increased YAP/TAZ activity.

Methods and Results: We assessed normal and fibrotic (IPF or intratracheal... (More)
Objective: Idiopathic pulmonary fibrosis (IPF) is a devastating disease with no cure and is characterized by deranged epithelial repair, myofibroblast activation, and excess deposition of extracellular matrix. Yes associated protein (YAP) and transcriptional co-regulator with PDZ-binding domain(TAZ), co-transcriptional activators of the Hippo pathway and proto-oncogenes, were recently found to be deranged in IPF. The cause of their dysregulation remain unknown. Hippo signaling regulates several endogenous progenitor cell functions through YAP/TAZ. We hypothesized that Hippo signaling is downregulated in IPF, resulting in increased YAP/TAZ activity.

Methods and Results: We assessed normal and fibrotic (IPF or intratracheal bleomycin-treated murine) lung tissue using immunohistochemistry, qPCR, and Gene Set Enrichment Analysis to identify cell types with deranged YAP/TAZ. Distal epithelial cells and fibroblasts were found to have dysregulated YAP/TAZ activity. Hippo components were downregulated in IPF and fibrotic mice, including in murine alveolar type II cells (mATII). Secretion of YAP/TAZ targets with pro-fibrotic activity was increased in fibrotic mATII as detected by mass spectrometry proteomics. Principal component analysis using Hippo expression in the Lung Gene Research Consortium separated IPF from normal patients. Fibrotic markers, including YAP/TAZ targets and myofibroblast activation, were reduced in the bleomycin model of fibrosis and in a novel ex vivo model of early pulmonary fibrosis in human precision cut lung slices when verteporfin, an FDA approved drug and YAP/TAZ inhibitor, was used therapeutically.

Conclusion: Hippo-YAP/TAZ are deranged in IPF. Pharmaceutical targeting of YAP/TAZ and or restoration of Hippo signaling may represent a new therapeutic strategy for IPF. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
European Respiratory Journal1988-01-01+01:00
volume
50
issue
Suppl. 61
publisher
Eur Respiratory Soc
ISSN
0903-1936
DOI
10.1183/1393003.congress-2017.OA475
language
English
LU publication?
yes
id
a3e0f54a-8677-45e4-a427-186811d856e3
alternative location
http://erj.ersjournals.com/lookup/doi/10.1183/1393003.congress-2017.OA475
date added to LUP
2018-01-04 16:46:11
date last changed
2018-01-12 12:14:08
@misc{a3e0f54a-8677-45e4-a427-186811d856e3,
  abstract     = {Objective: Idiopathic pulmonary fibrosis (IPF) is a devastating disease with no cure and is characterized by deranged epithelial repair, myofibroblast activation, and excess deposition of extracellular matrix. Yes associated protein (YAP) and transcriptional co-regulator with PDZ-binding domain(TAZ), co-transcriptional activators of the Hippo pathway and proto-oncogenes, were recently found to be deranged in IPF. The cause of their dysregulation remain unknown. Hippo signaling regulates several endogenous progenitor cell functions through YAP/TAZ. We hypothesized that Hippo signaling is downregulated in IPF, resulting in increased YAP/TAZ activity.<br/><br/>Methods and Results: We assessed normal and fibrotic (IPF or intratracheal bleomycin-treated murine) lung tissue using immunohistochemistry, qPCR, and Gene Set Enrichment Analysis to identify cell types with deranged YAP/TAZ. Distal epithelial cells and fibroblasts were found to have dysregulated YAP/TAZ activity. Hippo components were downregulated in IPF and fibrotic mice, including in murine alveolar type II cells (mATII). Secretion of YAP/TAZ targets with pro-fibrotic activity was increased in fibrotic mATII as detected by mass spectrometry proteomics. Principal component analysis using Hippo expression in the Lung Gene Research Consortium separated IPF from normal patients. Fibrotic markers, including YAP/TAZ targets and myofibroblast activation, were reduced in the bleomycin model of fibrosis and in a novel ex vivo model of early pulmonary fibrosis in human precision cut lung slices when verteporfin, an FDA approved drug and YAP/TAZ inhibitor, was used therapeutically.<br/><br/>Conclusion: Hippo-YAP/TAZ are deranged in IPF. Pharmaceutical targeting of YAP/TAZ and or restoration of Hippo signaling may represent a new therapeutic strategy for IPF.},
  articleno    = {OA475},
  author       = {Wagner, Darcy and Alsafadi, Hani and Mutze, Kathrin and Costa, Rita and Stein, Marlene and Schiller, Herbert and Kaminski, Naftali and Koenigshoff, Melanie},
  issn         = {0903-1936},
  language     = {eng},
  month        = {09},
  note         = {Conference Abstract},
  number       = {Suppl. 61},
  publisher    = {Eur Respiratory Soc},
  series       = {European Respiratory Journal1988-01-01+01:00},
  title        = {LSC - 2017 - Hippo-YAP/TAZ signaling is deranged in IPF},
  url          = {http://dx.doi.org/10.1183/1393003.congress-2017.OA475},
  volume       = {50},
  year         = {2017},
}