Chemogenomics to Identify New Molecular Targets in PF

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DESCRIPTION (provided by applicant): 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.