Reversing mechanical stress induced remodelling in idiopathic pulmonary fibrosis

逆转特发性肺纤维化中机械应力诱导的重塑

• 批准号: 317816228
• 负责人: Professorin Dr. Antje Prasse
• 金额: --
• 依托单位: Klinik für Pneumologie und Infektiologie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/317816228?language=en
• 关键词: Reversing; mechanical; stress; induced; remodelling

Idiopathic pulmonary fibrosis (IPF) is a fatal disease with a mean survival time of 3 years. New treatment options are urgently warranted. IPF is characterized by a vast remodeling of the alveolar compartment which results in a loss of alveoli and replacement by non-functional replacement tissue and scarring. Mechanical stress is fundamentally linked to the pathogenesis of IPF and thought to drive the disease by TGF-beta activation. The exact mechanisms induced by mechanical stress however are only rudimentarily understood. The intended project aims to investigate mechanisms induced by increased mechanical load in IPF applying molecular biology and new imaging techniques. The focus lies on TGF-beta signaling induced by mechanical stress and the role of avbeta6 integrin and CXCR4 in this context. In mice and humans with pulmonary fibrosis CXCR4 and avbeta6 integrin will be imaged by positron emission tomography (PET) in vivo and correlated with cell and molecular biology findings. In addition, we will use the organ care system (OCS) to image mechanical stress in explanted IPF lungs by newly developed algorithms based on computer tomography (CT) scanning. On the basis of our achievements we will develop new therapeutical strategies which utilize the CXCR4, avbeta6 and PDGF radio nuclear tracers bound to alpha emitters. Treatment effects will be tested in a humanized mice model and in explanted lungs using the OCS. Moreover extra corporal membrane oxygenation (ECMO) and the organ care system will be evaluated as temporal unloading of mechanical stress to allow reverse remodelling.

特发性肺纤维化（IPF）是一种致死性疾病，平均生存时间为3年。迫切需要新的治疗方案。IPF的特征是肺泡室的大量重塑，导致肺泡丧失并被非功能性替代组织和瘢痕替代。机械应力从根本上与IPF的发病机制相关，并被认为通过TGF-β激活驱动疾病。然而，由机械应力引起的确切机制仅被初步理解。该项目旨在应用分子生物学和新的成像技术研究IPF中机械负荷增加引起的机制。重点在于机械应力诱导的TGF-β信号传导和avbeta 6整合素和CXCR 4在此背景下的作用。在患有肺纤维化的小鼠和人类中，CXCR 4和α v β 6整联蛋白将通过体内正电子发射断层扫描（PET）成像，并与细胞和分子生物学发现相关联。此外，我们将使用器官护理系统（OCS），通过基于计算机断层扫描（CT）的新开发算法，对IPF肺的机械应力进行成像。在我们的成就的基础上，我们将开发新的治疗策略，其利用与α发射体结合的CXCR 4、avbeta 6和PDGF放射性核示踪剂。将在人源化小鼠模型中和使用OCS的肺移植中测试治疗效果。此外，体外膜氧合（ECMO）和器官护理系统将被评价为机械应力的暂时卸载，以允许逆向重塑。