Targeting the ADAM10-sEphrin-B2 pathway in pulmonary fibrosis

靶向 ADAM10-sEphrin-B2 通路治疗肺纤维化

• 批准号: 9894849
• 负责人: David Lagares
• 金额: $ 42万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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/9894849
• 关键词: Biological; Bleomycin; Blocking Antibodies; Cells; Cicatrix; Cleaved cell; 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; Prognostic Marker; Pulmonary Fibrosis; Receptor Signaling; Respiratory physiology; Rho-associated kinase; Signal Transduction; Slice; Structure of parenchyma of lung; Therapeutic; Tissues; Treatment Efficacy; autocrine; design; driving force; efficacy testing; experimental study; idiopathic pulmonary fibrosis; in vivo; indium-bleomycin; inhibitor/antagonist; lung development; lung injury; mortality; mouse model; neutralizing antibody; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; paracrine; pre-clinical; prevent

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.

项目摘要/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疤痕。 具有最常见形式的特发性肺纤维化（IPF）的患者患有不可逆的患者 最终是致命的间质性肺疾病，其特征是肺功能逐渐下降，最终 阻碍呼吸的能力。激活疤痕形成细胞称为肌纤维细胞是驱动力 在渐进式肺疤痕后，过度细胞外基质（ECM）沉积和组织重塑 与肺纤维化有关。因此，鉴定分子介质指导 肌纤维细胞激活不仅会进一步增强我们对肺纤维化发病机理的理解， 但也为新型抗纤维化疗法提供了合理的治疗靶标。我们最近确定了 ADAM10-Sephrin-B2途径是IPF患者和小鼠患者的肌纤维细胞激活的主要驱动力 肺纤维化模型。我们最近的研究表明，在肺损伤后，全部 - 静止的肺成纤维细胞中的长度ephrin-b2被拆解蛋白和金属蛋白酶蛋白水解裂解 ADAM10，导致生物活性分子可溶性Ephrin-B2（Sephrin-B2）产生。一次 Shed，Sephrin-B2通过激活EPHB4受体生成对静态成纤维细胞的促纤维化信号传导 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 促进静止的成纤维细胞分化为活化的肌纤维细胞，足以驱动组织 体内小鼠的纤维化。此外，在肺成纤维细胞中特别缺乏ephrin-b2的小鼠表现出 不受博来霉素诱导的肺纤维化的明显保护。因此，我们假设该策略 通过靶向ADAM10或直接阻止Sephrin-B2，中断Sephrin-B2的阐述 作为肺纤维化的新型治疗策略的潜力。该应用中提出的研究是 旨在定义ADAM10-塞普林-B2途径驱动肺纤维化的生物学机制 并制定新的治疗策略来抑制IPF患者的这种途径。具体来说，我们建议 四个具体目的：（1）确定ADAM10在体内产生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 在体外诱导肌纤维细胞激活，（3）确定抗塞弗林-B2的治疗功效 临床前和人类IPF模型中的中和抗体，（4）评估血浆Sephrin-B2水平为 IPF中一种新颖的预后生物标志物。本应用程序中提出的实验将描绘出小说 ADAM10-Sephrin-B2途径的机制可促进肺纤维化。我们还将确定 该途径的治疗封锁是否有可能成为有效的新治疗策略 IPF，一种无法治愈的致命疾病。