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Chitinase1 Regulation of Pulmonary Fibrosis and Therapeutic Targeting

Award Number: R01HL155558
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Chitinase1 Regulation of Pulmonary Fibrosis and Therapeutic Targeting - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Lung Diseases Research	000	4	12/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $398,750 )
2024	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Lung Diseases Research	000	4	8/15/2024	NON-COMPETING CONTINUATION	$398,750
														Subtotal = $398,750

Issue Date FY: 2023 ( Subtotal = $398,750 )
2023	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Lung Diseases Research	000	3	6/26/2023	NON-COMPETING CONTINUATION	$398,750
														Subtotal = $398,750

Issue Date FY: 2022 ( Subtotal = $398,750 )
2022	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Lung Diseases Research	000	2	6/2/2022	NON-COMPETING CONTINUATION	$398,750
														Subtotal = $398,750

Issue Date FY: 2021 ( Subtotal = $397,500 )
2021	2021	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Lung Diseases Research	000	1	9/14/2021	NEW	$397,500
														Subtotal = $397,500

Grand Total All Awards = $1,593,750

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Chitinase1 Regulation of Pulmonary Fibrosis and Therapeutic Targeting

Award Number: R01HL155558

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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