Targeting the alpha v integrin mechanotransduction axis in IPF

 描述（由申请人提供）：特发性肺纤维化或IPF是一种影响多达50万美国人的终末期疾病，没有FDA批准的能够阻止疾病进展的治疗。该疾病的特征在于细胞外基质（ECM）被称为“肌成纤维细胞”的活化成纤维细胞过度组装。最近，研究已经证明，组织力学，特别是由ECM的肌成纤维细胞组装和收缩引起的组织硬度，能够驱动肌成纤维细胞的分化，从而驱动疾病进展。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进展。尽管有这些最新的发现，我们仍然不知道这个过程是如何开始的，我们也没有任何有效阻止疾病进展的疗法。在目前的研究建议中，我们假设，一个新兴的成纤维细胞亚群显示失调的机械转导表型，由于这些细胞无法“感觉”他们的环境的刚度。这些成纤维细胞是 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对异常成纤维细胞机械转导的正常化。我们将使用从人类到小鼠的大量细胞来源，从纯合成到人类疾病衍生的模型ECM，以及疾病的动物模型，沿着先进的生物物理和细胞生物学测定来完成该项目。本申请中提出的研究不仅在 它对特发性肺纤维化临床诊断和治疗的潜在影响，也对我们理解肺内从正常伤口愈合过渡到纤维化进展的机制基础产生影响。

 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.