In addition to intermittent, reversible obstruction, some asthmatics, develop fixed airway obstruction knownas remodeling. A growing literature suggests thatTGFpt produced by activated and long-lived airway andparenchymal eosinophils (EOS) induces hyperplasia of bronchiolar fibroblasts, smooth muscle andmyoepithelial cells culminating with enhanced production of collagens and extracellular matrix proteins.Remodeling is reduced when eosinophils are eliminated from the airways suggesting that suppression ofEOS 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 productionand signaling. Pin1 is related to cyclophilin A and FKBP and is the only known eukaryotic enzyme that bindsto and catalyzes the cis-trans isomerization of phosphoserine-proline or phosphothreonine-proline peptidebonds. The isomerization of target proteins alters their conformation, function or stability. Pin1 has recentlybeen implicated in GM-CSF mRNA metabolism, suggesting a broader role in the regulation of cytokinebiogenesis by activated EOS. We now present evidence that Pin1 regulates TGFpl expression by EOS andTGFpl signaling in fibroblasts. Specific blockade of PinVs PPIase activity in EOS reduced TGFpl mRNAstability, 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 theregulation of TGFpl mRNA decay or gene expression. Pin1 inhibition reduced collagen mRNA accumulationin bronchial airway derived fibroblasts exposed to TGFpl in vitro as well as in the airways, bronchoalveolarlavage (BAL) cells and lung parenchyma of allergic rat models of asthma treated in vivo. Therefore, wehypothesize that Pin1 is a critical, signaling intermediate that plays a key role in the production and action ofTGFpl in the asthmatic lung. We therefore propose to: 1. Identify how Pin1 isomerase activity is regulatedafter eosinophil activation, 2. Determine how Pin1 protein targets HuR and AUF1 control TGFpl mRNAdecay, 3. Determine how Pin1 regulates TGFpl signaling in fibroblasts and 4, Determine if Pin1 blockadecan alter airway remodeling in animal models of chronic allergen exposure. In aggregate these studies willclarify the role and function of Pin1 in asthma pathogenesis and airway remodeling.
| Moon, Hyung-Geun; Kim, Seung-Jae; Jeong, Jong Jin et al. (2018) Airway Epithelial Cell-Derived Colony Stimulating Factor-1 Promotes Allergen Sensitization. Immunity 49:275-287.e5 |
| Khoury, Paneez; Akuthota, Praveen; Ackerman, Steven J et al. (2018) Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD). J Leukoc Biol 104:69-83 |
| Johansson, Mats W; Kelly, Elizabeth A; Nguyen, Christopher L et al. (2018) Characterization of Siglec-8 Expression on Lavage Cells after Segmental Lung Allergen Challenge. Int Arch Allergy Immunol 177:16-28 |
| Evans, Michael D; Esnault, Stephane; Denlinger, Loren C et al. (2018) Sputum cell IL-1 receptor expression level is a marker of airway neutrophilia and airflow obstruction in asthmatic patients. J Allergy Clin Immunol 142:415-423 |
| Esnault, Stephane; Hebert, Alexander S; Jarjour, Nizar N et al. (2018) Proteomic and Phosphoproteomic Changes Induced by Prolonged Activation of Human Eosinophils with IL-3. J Proteome Res 17:2102-2111 |
| Bortnov, Valeriu; Annis, Douglas S; Fogerty, Frances J et al. (2018) Myeloid-derived growth factor is a resident endoplasmic reticulum protein. J Biol Chem 293:13166-13175 |
| Schwantes, Elizabeth A; Evans, Michael D; Cuskey, Alex et al. (2018) Elevated fractional exhaled nitric oxide and blood eosinophil counts are associated with a 17q21 asthma risk allele in adult subjects. J Asthma Allergy 11:1-9 |
| Tomasini-Johansson, Bianca R; Mosher, Deane F (2018) Microtiter assays for quantitation of assembly of plasma and cellular fibronectin. Methods Cell Biol 143:157-170 |
| Turton, Keren B; Wilkerson, Emily M; Hebert, Alex S et al. (2018) Expression of novel ""LOCGEF"" isoforms of ARHGEF18 in eosinophils. J Leukoc Biol 104:135-145 |
| Bernau, Ksenija; Leet, Jonathan P; Esnault, Stephane et al. (2018) Eosinophil-degranulation products drive a proinflammatory fibroblast phenotype. J Allergy Clin Immunol 142:1360-1363.e3 |
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