Phosphorylation Control of Fibroproliferative ARDS

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PROJECT SUMMARY This proposal represents a five-year research career development plan aimed at better understanding the development of pathogenic pulmonary fibrogenesis following acute lung injury. The candidate is an Assistant Professor of Medicine at the University of Colorado in the Division of Pulmonary Sciences and Critical Care Medicine. The outlined proposal builds on her strong background in basic science research and develops new translational research skills under the mentorship of Drs. Gregory Downey and Ellen Burnham. The proposed research plan, didactics, hands-on workshops, and bench-side learning will position the candidate with a unique set of cross-disciplinary skills that will enable her transition to independence as a basic and translational physician-scientist in the fields of lung injury and fibrosis. The acute respiratory distress syndrome (ARDS) is a major healthcare problem in the US. Many ARDS survivors experience impaired long-term outcomes due to the development of pathologic pulmonary fibroproliferation. This excessive fibroproliferation, termed fibroproliferative ARDS (FP-ARDS), is characterized by early, over- exuberant fibroproliferative responses with accumulation of myofibroblasts and deposition of extracellular matrix, due in part to increases in TGF-β. The ability to predict patients at risk for developing FP-ARDS will assist with prognostication, targeting interventions, and the development of specific therapies. Protein Tyrosine Phosphatase (PTP)-α is a widely expressed receptor-type tyrosine phosphatase. Mice genetically deficient in PTPα (Ptpra-/-) are protected in models of pulmonary fibrosis via mechanisms affecting cellular responsiveness to TGF-β. This proposal will evaluate the role of PTPα in the pathogenesis of FP-ARDS and test the hypothesis that inhibition of PTPα will prevent pathologic fibroproliferation in ARDS by attenuating TGF-β signals in fibroblasts. The candidate will address three main research aims. Specific Aim 1 will focus on whether PTPα is required for fibroproliferative responses in ARDS. Murine models of FP-ARDS, including intra- tracheal hydrochloric acid and H1N1 influenza will be utilized to determine if genetic absence of PTPα provides protection from the development of fibroproliferation. Cell-type specific knockout of PTPα will further assist in characterizing the role PTPα plays in key lung parenchymal cells. The goal of Specific Aim 2 is to better understand the cellular mechanisms by which PTPα promotes profibrotic pathways in lung fibroblasts, with a particular focus on TGF-β receptors and Src kinase. Specific Aim 3 leverages previously and prospectively collected human bronchoalveolar lavage (BAL) fluid to better quantify the profibrotic environment in the lungs of ARDS patients and determine if PTPα augments these fibroproliferative responses. In vitro experiments will characterize cellular profibrotic responses to human ARDS BAL and correlate these responses with the long- term clinical course of ARDS patients. A long-term goal of this proposal is to translate our anticipated findings into the development of therapies for patients with ARDS.