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Chitinase1 Regulation of Pulmonary Fibrosis and Therapeutic Targeting

几丁质酶1对肺纤维化的调节和治疗靶向

基本信息

批准号：
10633256
负责人：
CHUN GEUN LEE
金额：
$ 39.88万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10633256
关键词：
Animal Model Bacterial Infections Binding Binding Proteins Biology Chitin Chitinase Chronic Obstructive Pulmonary Disease Circulation Disease Enzyme Tests Evaluation Extracellular Matrix Feedback Fibroblasts Fibrosis Gene Expression Gene Family Gene Proteins Generations Health Human Hydrolase Individual Inflammation Interstitial Lung Diseases Intervention Knowledge Libraries Life Lung Lung diseases Lysosomal Storage Diseases Macrophage Activation Mediating Mediator Mission Mutant Strains Mice Mycoses Myofibroblast Nature Nuclear Ozone Pathogenesis Patients Pharmaceutical Preparations Phosphorylation Play Polysaccharides Preventive Prokaryotic Cells Proliferating Proteins Pulmonary Fibrosis Regulation Reporting Research Role Sarcoidosis Scleroderma Signal Transduction Testing Therapeutic Therapeutic Effect Therapeutic Uses Time Tissues Transforming Growth Factor beta Transforming Growth Factor beta Receptors Transforming Growth Factors Treatment Efficacy United States National Institutes of Health disability enzyme activity idiopathic pulmonary fibrosis in vivo indium-bleomycin inhibitor insight man novel response screening small molecule therapeutic target therapeutically effective trafficking

项目摘要

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.

项目摘要壳三糖苷酶（Chitotriosidase，Chitinase 1; Chit 1）是人类体内主要的真几丁质酶。它可以在流通中找到，并且在以炎症、组织炎性疾病、炎症性疾病、炎症性疾病和炎症性疾病为特征的多种疾病中进一步增加。重塑和/或纤维化，包括细菌或真菌感染，溶酶体贮积病（戈谢病），结节病、慢性阻塞性肺病（COPD）和间质性肺病。然而，具体作用 Chit 1在这些疾病发病机制中的作用尚未阐明。最近我们报道Chit 1增强了转化生长因子-β1（TGF-β1）是健康和疾病中组织纤维化的关键介质，导致硬皮病相关的间质性肺病（SSc-ILD）的发病机制。但 Chit 1用于调节纤维化组织反应的机制以及这些机制在特发性肺纤维化尚未明确定义。在初步研究中，我们证明Chit 1 增强促纤维化巨噬细胞活化、TGF-β1刺激的成纤维细胞增殖、肌成纤维细胞分化、细胞外基质基因表达和蛋白质积累。重要的是，这些影响是通过Chit 1抑制TGF-β1对其反馈抑制剂Smad 7的诱导的能力介导。Chit 1与 TGF-β受体相关蛋白1（Tgfbrap 1）和叉头盒O3（FoxO 3）在TGF-β受体相关蛋白1和FoxO 3之间起着关键作用。在Chit 1增强TGF-β1信号传导和效应器反应中的作用，FoxO 3在TGF-β1信号传导和效应器反应中起关键作用。 β1诱导Samd 7。通过广泛的药物库筛选，我们确定春雷霉素（KSM）是一种小分子药物，强烈抑制Chit 1酶活性的分子，并测试了其在博来霉素诱导的肺纤维化在这项评估中，KSM在预防和治疗方面都显示出令人印象深刻的抗纤维化作用。治疗条件。这些发现使我们提出一个假设，Chit 1和它的相互作用伙伴是潜在的用于干预肺纤维化和KSM的治疗靶点可以被开发为一类新的治疗靶点，肺纤维化患者的治疗药物。为了验证这个假设，我们将目标1.明确Tgfbrap 1在Chit 1介导的肺纤维化中的作用及机制。目标二。在TGF-β刺激的肺纤维化中表征Chit 1对FoxO 3和Smad 7的调节。目标3。描述春雷霉素（KSM）作为Chit 1抑制剂在肺纤维化中的治疗用途。