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: 9392809
• 负责人: Thomas Harrison Barker
• 金额: $ 31.11万
• 依托单位: UNIVERSITY OF VIRGINIA
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9392809
• 关键词: Targeting; alpha; integrin; mechanotransduction; axis

 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（由申请人提供）：特发性肺纤维化 (IPF) 是一种影响多达 500,000 名美国人的绝症，目前尚无 FDA 批准的能够阻止疾病进展的疗法。该疾病的特征是细胞外基质 (ECM) 过度组装。激活的成纤维细胞被称为“肌成纤维细胞”，最近的研究表明，组织力学，特别是由肌成纤维细胞组装而成的组织硬度。简而言之，肌成纤维细胞能够募集更多的肌成纤维细胞，导致疾病不受控制地进展，但我们仍然不了解该过程是如何启动的。我们有任何有效阻止疾病进展的疗法，在当前的研究提案中，我们追求的是，​​由于这些细胞无法进行机械传导表型，新兴的成纤维细胞亚群表现出失调的表型。这些成纤维细胞能够“感知”其环境的僵硬程度。 因此，即使在柔软的环境中，也能够像肌成纤维细胞一样组装和收缩 ECM，从而使基质从正常偏向促纤维化。我们建议定义异常表型，确定分子机制，并提出一种使纤维化正常化的新方法。我们将使用从人类到小鼠的多种细胞来源、从纯合成到人类疾病衍生的模型 ECM、疾病动物模型以及先进的生物物理学和细胞生物学测定来完成该项目，该申请中提出的研究不仅在以下方面具有重要意义。 它对 IPF 的临床诊断和治疗的潜在影响，而且对我们理解从正常伤口愈合到肺内纤维化进展转变的机制基础的影响。