Targeting the alpha v integrin mechanotransduction axis in IPF

靶向 IPF 中的 α v 整合素机械转导轴

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：特发性肺纤维化（IPF）是一种最终疾病，影响了多达500,000名美国人，没有FDA批准的疗法，能够停止疾病进展。该疾病的特征是通过称为“肌纤维细胞”的活化成纤维细胞组装过细胞外基质（ECM）。最近，研究表明，组织力学，特别是由ECM和收缩的肌成纤维细胞组装引起的组织刚度，能够推动肌纤维细胞的分化，从而驱动疾病进展。简而言之，肌纤维细胞能够募集更多的肌纤维细胞，从而导致不受限制地进展的疾病。尽管最近发现了这些发现，但我们仍然不了解该过程是如何启动的，我们也没有任何有效停止疾病进展的疗法。在当前的研究建议中，我们假设出现的成纤维细胞亚群显示出失调的机械转移表型，因为这些细胞无法“感知”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，例如肌纤维细胞，从而使基质从正常到纤维化偏向。我们将建议定义异常表型，识别分子机制，并提出一种新颖的方法来正常化成纤维细胞机械传导。我们将使用从人到小鼠的许多细胞来源，从纯合成到人类疾病衍生的ECM，以及疾病的动物模型，以及先进的生物物理和细胞生物学测定法，以完成该项目。本应用程序中提出的研究不仅在它对IPF的临床诊断和治疗的潜在影响，以及它对我们对从正常伤口愈合到肺内纤维化进展的机械基础的理解的影响。