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：
10372067
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10372067
关键词：
Biological Bleomycin Blocking Antibodies 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 of activation protein 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.

项目概要/摘要肺纤维化是一种致命的肺部疾病，其特征是肺部进行性破坏和结疤。患有最常见形式特发性肺纤维化 (IPF) 的患者患有不可逆的和最终致命的间质性肺疾病，其特征是肺功能逐渐下降，最终阻碍呼吸能力。称为肌成纤维细胞的疤痕形成细胞的激活是驱动力进行性肺部疤痕形成、过度细胞外基质 (ECM) 沉积和组织重塑与肺纤维化有关。因此，指导分子介质的鉴定肌成纤维细胞的激活，不仅将进一步增进我们对肺纤维化发病机制的认识，同时也为新型抗纤维化疗法提供合理的治疗靶点。我们最近确定了 ADAM10-sEphrin-B2 通路是 IPF 患者和小鼠肌成纤维细胞激活的主要驱动因素肺纤维化模型。我们最近的研究表明，肺损伤后，全功能胞外域静止肺成纤维细胞中的长度肝配蛋白-B2被解整合素和金属蛋白酶进行蛋白水解切割 ADAM10，导致生物活性分子可溶性 Ephrin-B2 (sEphrin-B2) 的生成。一次脱落后，sEphrin-B2 通过激活 EphB4 受体向静止成纤维细胞产生促纤维化信号以自分泌/旁分泌方式发出信号。我们的研究表明 sEphrin-B2/EphB4 受体信号传导促进静止成纤维细胞分化为活化的肌成纤维细胞，并足以驱动组织小鼠体内纤维化。此外，肺成纤维细胞中基因缺乏肝配蛋白 B2 的小鼠表现出对博来霉素诱导的肺纤维化有显着的保护作用。因此，我们假设策略通过靶向 ADAM10 或直接阻断 sEphrin-B2 来中断 sEphrin-B2 的精制，具有作为肺纤维化新治疗策略的潜力。本申请中提出的研究是旨在定义 ADAM10-sEphrin-B2 通路驱动肺纤维化的生物学机制并开发新的治疗策略来抑制 IPF 患者的这一通路。具体来说，我们建议四个具体目标：(1) 确定 ADAM10 在体内生成 sEphrin-B2 的细胞机制并有助于肺纤维化的发展，(2) 研究 sEphrin-B2 的机制体外诱导肌成纤维细胞活化，(3) 确定抗 sEphrin-B2 的治疗效果临床前和人类 IPF 模型中的中和抗体，以及 (4) 评估血浆 sEphrin-B2 水平： IPF 的一种新型预后生物标志物。本申请中提出的实验将描述新颖的 ADAM10-sEphrin-B2 通路促进肺纤维化的机制。我们还将确定对该通路的治疗性阻断是否有可能成为一种有效的新治疗策略 IPF，一种无法治愈且致命的疾病。