# Chitinase1 Regulation of Pulmonary Fibrosis and Therapeutic Targeting

> **NIH NIH R01** · BROWN UNIVERSITY · 2021 · $397,500

## Abstract

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.

## Key facts

- **NIH application ID:** 10100042
- **Project number:** 1R01HL155558-01
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** CHUN GEUN LEE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $397,500
- **Award type:** 1
- **Project period:** 2021-09-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10100042

## Citation

> US National Institutes of Health, RePORTER application 10100042, Chitinase1 Regulation of Pulmonary Fibrosis and Therapeutic Targeting (1R01HL155558-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10100042. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*