Activation of redox-sensitive transcription factor, activator protein-1 (AP-1) is associated with profibrotic gene expression and is regulated by redox proteins, macrophage inhibitory factor (MIF) and redox effector factor-1 (Ref-1). Transforming growth factor Beta(TGFBeta), a key mediator in the development of airway fibrosis, is important in cell proliferation and differentiation, apotosis, and deposition of ECM. TGFB signaling activates both Smad (anti-proliferative/immunosuppressive) and AP-1 (profibrotic) transcription pathways. TGFBeta in the airways of patients with pulmonary fibrosis (PF) may function initially as a """"""""healing molecule"""""""" involved in the diminution of initial airway inflammation and in tissue repair. However, with continued inflammatory response such as may occur in PF, the balance may be shifted, via increased AP-1-mediated transcription, to excessive ECM deposition and development of airway fibrosis. Selective inhibition of TGFBeta- induced AP-1 signal transduction (without affecting Smad transcription) by inhibition of Ref-1 or MIF could theoretically prevent TGFBeta-mediated ECM accumulation and fibrosis and result in a predominantly antiproliferative, immunosuppressive response. In this proposal, we will utilize a novel chemogenomics approach to identify and validate small molecule inhibitors of AP-1 transcription and TGFB-driven profibrotic gene expression as potential therapies for PF patients.
Our Specific Aims are as follows:
Aim 1. To Develop Small Molecule Inhibitor(s) of TGFBeta-Mediated Pulmonary Fibrosis, Aim la. To Develop Small Molecule Redox MIF and Ref-1 Inhibitors of AP-1 Transcription.
Aim lb. To Identify Novel Small Molecule Inhibitors of TGFBeta-driven Proflbrotic Gene Expression.
Aim 2. To Determine the Effect of AP-1/TGFBeta Inhibitors on Airway Inflammation and Fibrosis In Vivo in Mouse Models of PF.
Aim 3, To Determine the Effect of AP-1/TGFBeta inhibitor(s) on Proflbrotic Gene Expression in Lung Tissue and Airway Epithelial Cells of Patients with PF. These studies represent a focused effort using chemogenomics to identify, develop, and validate small molecule inhibitors of AP-1/TGFBeta-driven profibrotic gene expression as novel therapies in PF patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073722-02
Application #
6802325
Study Section
Special Emphasis Panel (ZHL1-CSR-P (M1))
Program Officer
Reynolds, Herbert Y
Project Start
2003-09-18
Project End
2007-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
2
Fiscal Year
2004
Total Cost
$604,800
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Henderson Jr, William R; Ye, Xin; Lai, Ying et al. (2013) Key role of group v secreted phospholipase A2 in Th2 cytokine and dendritic cell-driven airway hyperresponsiveness and remodeling. PLoS One 8:e56172
Zhou, Beiyun; Liu, Yixin; Kahn, Michael et al. (2012) Interactions between ?-catenin and transforming growth factor-? signaling pathways mediate epithelial-mesenchymal transition and are dependent on the transcriptional co-activator cAMP-response element-binding protein (CREB)-binding protein (CBP). J Biol Chem 287:7026-38
Milosevic, Jadranka; Pandit, Kusum; Magister, Marcus et al. (2012) Profibrotic role of miR-154 in pulmonary fibrosis. Am J Respir Cell Mol Biol 47:879-87
Banerjee, Ena Ray; Laflamme, Michael A; Papayannopoulou, Thalia et al. (2012) Human embryonic stem cells differentiated to lung lineage-specific cells ameliorate pulmonary fibrosis in a xenograft transplant mouse model. PLoS One 7:e33165
Mavila, Nirmala; James, David; Utley, Sarah et al. (2012) Fibroblast growth factor receptor-mediated activation of AKT-ýý-catenin-CBP pathway regulates survival and proliferation of murine hepatoblasts and hepatic tumor initiating stem cells. PLoS One 7:e50401
Henderson Jr, William R; Chi, Emil Y; Ye, Xin et al. (2010) Inhibition of Wnt/beta-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis. Proc Natl Acad Sci U S A 107:14309-14
Banerjee, Ena Ray; Jiang, Yi; Henderson Jr, William R et al. (2007) Alpha4 and beta2 integrins have nonredundant roles for asthma development, but for optimal allergen sensitization only alpha4 is critical. Exp Hematol 35:605-17
Henderson Jr, William R; Chi, Emil Y; Bollinger, James G et al. (2007) Importance of group X-secreted phospholipase A2 in allergen-induced airway inflammation and remodeling in a mouse asthma model. J Exp Med 204:865-77
Henderson Jr, William R; Chiang, Gertrude K S; Tien, Ying-Tzang et al. (2006) Reversal of allergen-induced airway remodeling by CysLT1 receptor blockade. Am J Respir Crit Care Med 173:718-28
Henderson Jr, William R; Banerjee, Ena Ray; Chi, Emil Y (2005) Differential effects of (S)- and (R)-enantiomers of albuterol in a mouse asthma model. J Allergy Clin Immunol 116:332-40

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