Chitinase1 Regulation of Pulmonary Fibrosis and Therapeutic Targeting

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PROJECT SUMMARY Chitotriosidase (chitinase 1; Chit1) is the major true chitinase in humans. It can be found in the circulation of normal individuals and is further increased in a variety of diseases characterized by inflammation, tissue remodeling and/or fibrosis including bacterial or fungal infections, lysosomal storage diseases (Gaucher’s), sarcoidosis, chronic obstructive lung diseases (COPD) and interstitial lung diseases. However, specific role of Chit1 in the pathogenesis of these diseases have not been elucidated. Recently we reported that Chit1 augments the effects of transforming growth factor-β1 (TGF-β1), a critical mediator of tissue fibrosis in health and disease, contributes to the pathogenesis of interstitial lung disease associated with Scleroderma (SSc-ILD). However, the mechanisms that Chit1 uses to regulate fibrotic tissue responses and the importance of these mechanisms in idiopathic pulmonary fibrosis have not been clearly defined. In preliminary studies, we demonstrate that Chit1 enhances profibrotic macrophage activation, TGF-β1-stimulated fibroblast proliferation, myofibroblast differentiation, extracellular matrix gene expression and protein accumulation. Importantly, these effects are mediated by the ability of Chit1 to inhibit TGF-β1 induction of its feedback inhibitor, Smad7. Chit1 interacts with TGF-β receptor associated protein 1 (Tgfbrap1) and Forkhead Box O3 (FoxO3) with Tgfbrap1 playing a critical role in Chit1 enhancement of TGF-β1 signaling and effector responses and FoxO3 playing a critical role in TGF- β1 induction of Samd7. Through extensive drug library screening, we identified Kasugamycin (KSM) as a small molecule that strongly inhibits Chit1 enzyme activity and tested its therapeutic effect in bleomycin induced pulmonary fibrosis. In this evaluation, KSM showed an impressive anti-fibrotic effect in both preventive and therapeutic conditions. These findings led us to a hypothesis that Chit1 and its interacting partners are potential therapeutic targets for the intervention of pulmonary fibrosis and KSM can be developed as a new class of therapeutic drug for the patients with pulmonary fibrosis. To test this hypothesis, we will Aim 1. Define the specific role and mechanism of Tgfbrap1 in Chit1 mediated pulmonary fibrosis. Aim 2. Characterize Chit1 regulation of FoxO3 and Smad7 in TGF-β stimulated pulmonary fibrosis. Aim 3. Characterize the therapeutic use of Kasugamycin (KSM) as a Chit1 inhibitor in pulmonary fibrosis.