Targeting the alpha v integrin mechanotransduction axis in IPF

靶向 IPF 中的 α v 整合素机械转导轴

• 批准号: 9033145
• 负责人: Thomas Harrison Barker
• 金额: $ 7万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9033145
• 关键词: Adverse effects; Affect; American; Animal Disease Models; Antibodies; Automobile Driving; Binding; Biological Assay; Cell surface; Cells; Chemicals; Cicatrix; Cilengitide; Clinical; Clinical Treatment; Complex; Contracts; Data; Deposition; Directed Molecular Evolution; Disease; Disease Progression; ECM receptor; Environment; Extracellular Matrix; Extracellular Matrix Proteins; FDA approved; Feedback; Fibroblasts; Fibronectins; Fibrosis; Focal Adhesions; Hamman-Rich syndrome; Health; Human; Immunoglobulin Fragments; In Vitro; Integrin Binding; Integrin Inhibition; Integrin alphaV; Integrins; Knockout Mice; Link; Lung; Mechanics; Mediating; Methods; Modeling; Molecular; Molecular Conformation; Mutation; Myofibroblast; Phenotype; Phosphotransferases; Process; Publishing; Pulmonary Fibrosis; Pulmonology; Recruitment Activity; Reporting; Research; Research Proposals; Resistance; Role; Signal Transduction; Signaling Protein; Source; Structure; Structure of parenchyma of lung; System; Terminal Disease; Testing; Therapeutic Effect; Tissues; Work; Wound Healing; base; clinical Diagnosis; effective therapy; human disease; in vivo; inhibitor/antagonist; innovation; interdisciplinary approach; mimetics; mouse model; novel strategies; novel therapeutics; programs; protein expression; receptor binding; response; soft tissue; wound

 DESCRIPTION (provided by applicant): Idiopathic Pulmonary Fibrosis, or IPF, is a terminal disease affecting as many as 500,000 Americans with no FDA-approved therapies capable of stopping disease progression. The disease is characterized by excessive assembly of extracellular matrix (ECM) by activated fibroblasts termed `myofibroblasts'. Recently, studies have demonstrated that tissue mechanics, specifically tissue stiffness resulting from myofibroblasts assembly of ECM and contraction, is capable of driving the differentiation of myofibroblasts and thus disease progression. In short, myofibroblasts are capable of recruiting more myofibroblasts leading to a disease that progresses unchecked. Despite these recent findings we still do not understand how the process is initiated, nor do we have any therapies that effective halt disease progression. In the current research proposal we hypothesize that an emergent fibroblast subpopulation displays dysregulated mechanotransductive phenotypes due to an inability of these cells to "sense" the stiffness of their environment. These fibroblasts are thus capable of assembling and contracting the ECM, like myofibroblasts, even in soft environments, thus skewing the matrix from normal to pro-fibrotic. We propose to define the aberrant phenotypes, identify the molecular mechanism, and propose a novel approach toward the normalization of aberrant fibroblast mechanotransduction. We will use a host of cell sources from human to mouse, model ECMs from purely synthetic to human disease-derived, and animal models of disease along with advanced biophysical and cell biological assays to complete the project. The research proposed in this application is significant not only in terms of its potential impact on the clinical diagnosis and treatment of IPF, but also in its impact on our understanding of the mechanistic underpinnings of the transition from normal wound healing to fibrotic progression within the lung.

 描述(申请人提供)：特发性肺纤维化，或IPF，是一种晚期疾病，影响多达50万美国人，没有FDA批准的能够阻止疾病进展的治疗方法。这种疾病的特征是激活的成纤维细胞过度聚集细胞外基质(ECM)，称为肌成纤维细胞。最近的研究表明，组织力学，特别是肌成纤维细胞组装ECM和收缩所产生的组织硬度，能够驱动肌成纤维细胞的分化，从而推动疾病的进展。简而言之，肌成纤维细胞能够招募更多的肌成纤维细胞，导致疾病不受控制地发展。尽管有这些最近的发现，我们仍然不知道这个过程是如何启动的，我们也没有任何有效阻止疾病进展的治疗方法。在目前的研究方案中，我们假设新出现的成纤维细胞亚群表现出机械转导表型失调，这是由于这些细胞无法“感觉”其环境的僵硬。这些成纤维细胞是 因此，即使在柔软的环境中，也能够组装和收缩ECM，就像肌成纤维细胞一样，从而使基质从正常偏斜到促纤维化。我们建议定义异常表型，确定分子机制，并提出一种新的方法来正常化异常成纤维细胞的机械转导。我们将使用从人到小鼠的大量细胞来源，从纯合成到人类疾病衍生的细胞外基质模型，以及疾病的动物模型以及先进的生物物理和细胞生物学分析来完成该项目。在本申请中提出的研究不仅在以下方面具有重要意义 它不仅对IPF的临床诊断和治疗有潜在的影响，而且对我们理解从正常伤口愈合到肺内纤维化进展的机制基础也有影响。