Therapeutic Benefit of Hsp90 Inhibition in Pulmonary Fibrosis
Abstract
Our project aims to address the Peer Reviewed Medical Research Program topic area involving the discovery of new therapies for pulmonary fibrosis that can improve the health and well-being of all military Service members, Veterans, and beneficiaries. Idiopathic pulmonary fibrosis (IPF) is an incurable, disabling, and often fatal disease characterized by the distribution of fibrotic lesions predominantly in the peripheral areas of the lung. The advent of two Food and Drug Administration-approved therapies for IPF has energized the field, but the recognition that their side effect profiles are formidable and their effects are suppressive rather than remission-inducing or curative tempers enthusiasm. New and better drugs that affect how patients feel and function are sorely needed. The design of clinical trials has been forever changed; placebo controlled trials have suddenly become rare and new studies are focused on testing of combination therapies compared to the approved therapies alone. Achieving this goal will require a better understanding of the molecular mechanisms by which therapeutic targets drive dysregulated matrix remodeling that can be reversed by anti-fibrotic compounds. In our preliminary studies, we identified heat-shock protein 90 (HSP90) as a key regulator of gene programs that drive fibroblast activation leading to severe fibrotic lung disease. Further, our studies have found that HSP90 ATPase activity inhibitor called 17-AAG can markedly synergize with pirfenidone therapy to repress fibroblast activation involved in severe fibrotic lung disease. Here, we propose to identify mechanisms by which HSP90 functions as a positive driver of fibroblast activation. This discovery-based project has the potential to identify HSP90 inhibitors as a novel therapeutics to attenuate established and ongoing pulmonary fibrosis. The short-term impact upon completion of this 3-year study will result in the identification of HSP90 as a critical regulator of fibroblast activation. This research could have significant long-term impact on IPF care and research. In particular, this project will generate new understanding of the factors influencing IPF severity and mechanistically demonstrate how HSP90 activity contribute to the expansion of the fibrotic machinery in the pathology of IPF and provide new therapies for clinical interventions for patients with IPF.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710666
Entities
People
- Satish K Madala
Organizations
- United States Army