In addition to intermittent, reversible obstruction, some asthmatics, develop fixed airway obstruction known as remodeling. A growing literature suggests thatTGFpt produced by activated and long-lived airway and parenchymal eosinophils (EOS) induces hyperplasia of bronchiolar fibroblasts, smooth muscle and myoepithelial cells culminating with enhanced production of collagens and extracellular matrix proteins. Remodeling is reduced when eosinophils are eliminated from the airways suggesting that suppression of EOS derived TGFpl or blockade of its profibrotic signaling in cellular targets could have therapeutic benefits. Recently, we have identified Pin1, a peptidyl-prolyl isomerase (PPIase) as a participant in TGF(31 production and signaling. Pin1 is related to cyclophilin A and FKBP and is the only known eukaryotic enzyme that binds to and catalyzes the cis-trans isomerization of phosphoserine-proline or phosphothreonine-proline peptide bonds. The isomerization of target proteins alters their conformation, function or stability. Pin1 has recently been implicated in GM-CSF mRNA metabolism, suggesting a broader role in the regulation of cytokine biogenesis by activated EOS. We now present evidence that Pin1 regulates TGFpl expression by EOS and TGFpl signaling in fibroblasts. Specific blockade of PinVs PPIase activity in EOS reduced TGFpl mRNA stability, causing steady state mRNA levels and protein expression to significantly decline. Immunoprecipitation studies revealed that Pint binds to multiple proteins that have been implicated in the regulation of TGFpl mRNA decay or gene expression. Pin1 inhibition reduced collagen mRNA accumulation in bronchial airway derived fibroblasts exposed to TGFpl in vitro as well as in the airways, bronchoalveolar lavage (BAL) cells and lung parenchyma of allergic rat models of asthma treated in vivo. Therefore, we hypothesize that Pin1 is a critical, signaling intermediate that plays a key role in the production and action of TGFpl in the asthmatic lung. We therefore propose to: 1. Identify how Pin1 isomerase activity is regulated after eosinophil activation, 2. Determine how Pin1 protein targets HuR and AUF1 control TGFpl mRNA decay, 3. Determine how Pin1 regulates TGFpl signaling in fibroblasts and 4, Determine if Pin1 blockade can alter airway remodeling in animal models of chronic allergen exposure. In aggregate these studies will clarify the role and function of Pin1 in asthma pathogenesis and airway remodeling.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL088594-04
Application #
8217350
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
4
Fiscal Year
2011
Total Cost
$345,178
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Esnault, Stephane; Torr, Elizabeth E; Bernau, Ksenija et al. (2017) Endogenous Semaphorin-7A Impedes Human Lung Fibroblast Differentiation. PLoS One 12:e0170207
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Esnault, Stephane; Bernau, Ksenija; Torr, Elizabeth E et al. (2017) RNA-sequencing analysis of lung primary fibroblast response to eosinophil-degranulation products predicts downstream effects on inflammation, tissue remodeling and lipid metabolism. Respir Res 18:188
Shen, Zhong-Jian; Hu, Jie; Kashi, Venkatesh P et al. (2017) Epstein-Barr Virus-induced Gene 2 Mediates Allergen-induced Leukocyte Migration into Airways. Am J Respir Crit Care Med 195:1576-1585
Johansson, M W; Khanna, M; Bortnov, V et al. (2017) IL-5-stimulated eosinophils adherent to periostin undergo stereotypic morphological changes and ADAM8-dependent migration. Clin Exp Allergy 47:1263-1274
Kelly, Elizabeth A; Esnault, Stephane; Liu, Lin Ying et al. (2017) Mepolizumab Attenuates Airway Eosinophil Numbers, but Not Their Functional Phenotype, in Asthma. Am J Respir Crit Care Med 196:1385-1395

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