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Targeting the ADAM10-sEphrin-B2 pathway in pulmonary fibrosis

靶向 ADAM10-sEphrin-B2 通路治疗肺纤维化

基本信息

批准号：
10599961
负责人：
Benjamin David Medoff
金额：
$ 42万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599961
关键词：
Biological Bleomycin Blocking Antibodies Breathing Cells Cicatrix Clinical Data Deposition Disease Disintegrins Effector Cell Endothelial Cells EphB4 Receptor Ephrin-B2 Exhibits Extracellular Matrix Fibroblasts Fibrosis Generations Genetic Genetic study Human In Vitro Individual Interruption Interstitial Lung Diseases Length Ligands Lung Lung diseases Mediator Membrane Metalloproteases Modeling Molecular Morbidity - disease rate Mus Myofibroblast Names Pathogenesis Pathway interactions Patients Plasma Profibrotic signal Prognostic Marker Pulmonary Fibrosis Receptor Signaling Rho-associated kinase Slice Structure of parenchyma of lung Therapeutic Tissues Treatment Efficacy antifibrotic treatment autocrine design driving force efficacy testing experimental study fibrotic lung idiopathic pulmonary fibrosis in vivo indium-bleomycin inhibitor lung development lung injury mortality mouse model neutralizing antibody new therapeutic target novel novel therapeutic intervention paracrine pre-clinical prevent pulmonary function

项目摘要

Project Summary/Abstract Pulmonary fibrosis is a fatal lung disease characterized by progressive destruction and scarring of the lungs. Patients with the most common form, Idiopathic Pulmonary Fibrosis (IPF), suffer from irreversible and ultimately fatal interstitial lung disease characterized by progressive decline in lung function, ultimately impeding the ability to breathe. Activation of scar-forming cells named myofibroblasts is the driving force behind progressive lung scarring, excessive extracellular matrix (ECM) deposition and tissue remodeling associated with pulmonary fibrosis. Accordingly, the identification of the molecular mediators directing myofibroblast activation, will not only further enhance our understanding of the pathogenesis of lung fibrosis, but also provide rational therapeutic targets for novel anti-fibrotic therapies. We have recently identified the ADAM10-sEphrin-B2 pathway as a major driver of myofibroblast activation in patients with IPF and in mouse models of lung fibrosis. Our recent studies have demonstrated that following lung injury the ectodomain of full- length ephrin-B2 in quiescent lung fibroblasts is proteolytically cleaved by the disintegrin and metalloproteinase ADAM10, resulting in the generation of the biologically active molecule soluble Ephrin-B2 (sEphrin-B2). Once shed, sEphrin-B2 generates pro-fibrotic signaling to quiescent fibroblasts by activating EphB4 receptor signaling in an autocrine/paracrine manner. Our studies demonstrate that sEphrin-B2/EphB4 receptor signaling promotes differentiation of quiescent fibroblasts into activated myofibroblasts and is sufficient to drive tissue fibrosis in mice in vivo. Further, mice genetically lacking ephrin-B2 specifically in lung fibroblasts exhibit significant protection from bleomycin-induced lung fibrosis. Consequently, we hypothesize that strategies to interrupt the elaboration of sEphrin-B2, by targeting ADAM10, or blocking sEphrin-B2 directly, have the potential to serve as novel therapeutic strategies for lung fibrosis. The studies proposed in this application are designed to define the biological mechanisms by which the ADAM10-sEphrin-B2 pathway drives lung fibrosis and to develop novel therapeutic strategies to inhibit this pathway in patients with IPF. Specifically, we propose four specific aims: (1) To determine the cellular mechanisms by which ADAM10 generates sEphrin-B2 in vivo and contributes to the development of lung fibrosis, (2) To investigate the mechanisms by which sEphrin-B2 induces myofibroblast activation in vitro, (3) To determine the therapeutic efficacy of anti-sEphrin-B2 neutralizing antibodies in preclinical and human IPF models, and (4) To evaluate plasma sEphrin-B2 levels as a novel prognostic biomarker in IPF. The experiments proposed in this application will delineate novel mechanisms whereby the ADAM10-sEphrin-B2 pathway promotes lung fibrosis. We will also determine whether therapeutic blockade of this pathway has the potential to be an effective new therapeutic strategy for IPF, an incurable and deadly disease.

项目总结/文摘