Therapeutic Benefit of Hsp90 Inhibition in Pulmonary Fibrosis
Abstract
Pulmonary fibrosis is the final common pathway of a number of adult and pediatric diseases that are associated with fibroblast invasion and excessive deposition of the extracellular matrix (ECM) in the lung. In adults, fibrosis occurs in both the idiopathic pneumonias and in the systemic connective-tissue diseases. Idiopathic Pulmonary Fibrosis (IPF) is perhaps the most pernicious and enigmatic form of of lung fibrosis and recent evidence indicates that the prevalence the disease is increasing in the U.S. and around the world. Pirfenidone and nintedanib are two recently FDA-approved therapies that slow the rate of decline in lung function in patients with IPF, but do not halt or reverse fibrosis. Thus, newer therapies that reverse established fibrosis would have significant advantages over these current agents. Rationale: We have made the novel discovery that HSP90 functions as a master regulator of fibroblast activation and excessive deposition of ECM proteins in IPF using bioinformatics, molecular, and biochemical methods. Further, our preliminary data demonstrate that the beneficial effect of 17-AAG is mediated by inhibition of HSP90-dependent degradation of Wilms Tumor 1 (WT1), a novel fibroblast transcription factor that drives fibroblast activation and ECM production. Inhibition of HSP90 ATPase activity using the pharmacological inhibitor 17-AAG was sufficient to attenuate pulmonary fibrosis both in vitro and in vivo. Hypothesis: We will test the hypothesis that inhibition of HSP90 activity, coupled with anti-fibrotic actions of pirfenidone, will reverse established and progressive pulmonary fibrosis mediated by WT1-driven fibroblast dysfunction. Specific Aims: (1) To determine the role of HSP90 in fibroblast activation in IPF. For this aim, we will determine the role of HSP90AA, HSP90AB and dominant negative HSP90 in IPF fibroblast activation including proliferation, invasiveness, (myo)fibroblast survival and ECM production.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2022
- Accession Number
- AD1226089
Entities
People
- Satish K Madala