Role of fibrotic extracellular matrix in generating the IPF Fibroblast

纤维化细胞外基质在 IPF 成纤维细胞生成中的作用

• 批准号: 9187880
• 负责人: Peter B Bitterman
• 金额: $ 46.87万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-08 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9187880
• 关键词: Actins; Affect; Alpha Cell; Alveolar; American; Animal Model; Asphyxia; Automobile Driving; Biochemical; COL1A1 gene; COL1A2 gene; Cell Communication; Cell Differentiation process; Cell Surface Receptors; Cell division; Cells; Cessation of life; Cicatrix; Collagen; Collagen Type I; Cues; Data; Development; Disease; Disease Progression; Embryo; Extracellular Matrix; FDA approved; Feedback; Fibroblasts; Foundations; Gases; Gene Expression; Genes; Hamman-Rich syndrome; Human; Immunohistochemistry; In Vitro; Integrins; Kinetics; Knowledge; Lesion; Lung; Lung diseases; Maintenance; Measures; Mediating; Mesenchymal; Mesenchymal Stem Cells; Microscopy; Molecular; Muscle; Myofibroblast; PTEN gene; Pathogenesis; Pathologic; Patients; Persons; Pharmacological Treatment; Phenotype; Population; Positioning Attribute; Process; Production; Proliferating; Property; Publications; Publishing; Pulmonary Fibrosis; Reporter; Reporting; Resolution; Reticulum; Role; Sentinel; Signal Transduction; Smooth Muscle Actin Staining Method; Source; Surface; Time; Tissues; Treatment Efficacy; Work; Zebrafish; base; caveolin 1; drug discovery; embryo tissue; epigenetic regulation; in vivo; killings; molecular drug target; progenitor; promoter; public health relevance; receptor; stem; targeted treatment; therapy development; time interval

DESCRIPTION (provided by applicant): Idiopathic Pulmonary Fibrosis (IPF) is a lethal fibrotic lung disorder that kills 40,000 Americans each year and over 1 million persons worldwide. In IPF, relentless expansion and alteration of the alveolar mesenchymal cell population leads to production of diseased myofibroblasts that mediate progressive scarring of the gas exchange surface resulting in death by asphyxiation. Fibroblasts derived from the lungs of IPF patients have phenotypic hallmarks that distinguish them from their normal counterparts. IPF fibroblasts have altered integrin expression, are hyperproliferative, produce increased amounts of collagen, express increased amounts of �mooth muscle actin (�MA) and form fibrotic lesions in model organisms. We recently published that pathological lung mesenchymal progenitor cells (MPCs) are a cell-of-origin for the IPF fibroblast; and that IPF extracellular matrix (ECM) reprograms fibroblast gene expression to establish a positive feedback loop that translationally activates ECM genes and their cognate cell surface receptors. In this project we summarize our paradigm-shifting data. First, we show that IPF lungs MPCs - but not control lung MPCs - generate progeny with the in vitro and in vivo hallmarks of IPF fibroblasts. Next, we show that when primary lung fibroblasts (IPF or control) interact with decellularized lung ECM (IPF or control): i) the ECM source predominantly dictates gene expression; ii) IPF lung ECM translationally activates ECM genes and genes encoding their cognate integrin receptors; and iii) IPF lung ECM, but not control ECM, decreases fibroblast expression of miR29 - a potent negative regulator of ECM and proliferation genes - creating a positive feedback loop that provides a molecular mechanism for relentless disease progression. Based on this, we hypothesize that decellularized IPF lung ECM will direct human lung MPC differentiation towards the IPF phenotype; and stabilize that phenotype by epigenetic regulation of miR29 expression to create a positive feedback loop driving genes governing IPF fibroblast hallmarks. We propose 2 specific aims to elucidate the molecular mechanisms. Specific Aim 1: Genesis of the IPF fibroblast - Characterize the mechanisms by which MPCs acquire IPF phenotypic hallmarks on IPF lung ECM. Specific Aim 2: Disease Progression - Dissect the molecular and cellular mechanisms of the IPF ECM-driven positive feedback loop that increases integrin and ECM gene expression and suppresses their negative regulator, miR29. If we achieve our aims, our work will unveil mechanisms governing the genesis, maintenance and propagation of the IPF fibroblast and its pathological ECM. This information is foundational for developing therapies that target those ECM - mesenchymal cell interactions that drive IPF.

描述（由申请人提供）：特发性肺纤维化 (IPF) 是一种致命的纤维化肺部疾病，每年导致 40,000 名美国人和全世界超过 100 万人死亡。在IPF中，肺泡间充质细胞群的不断扩张和改变导致患病肌成纤维细胞的产生，介导气体交换表面进行性疤痕形成，导致窒息死亡。来自 IPF 患者肺部的成纤维细胞具有与正常成纤维细胞不同的表型特征。 IPF成纤维细胞整合素表达发生改变，过度增殖，产生更多量的胶原蛋白，表达更多量的平滑肌肌动蛋白（MA），并在模型生物体中形成纤维化病变。我们最近发表了病理性肺间充质祖细胞 (MPC) 是 IPF 成纤维细胞的起源细胞； IPF 细胞外基质 (ECM) 重新编程成纤维细胞基因表达，建立正反馈环，翻译激活 ECM 基因及其同源细胞表面受体。在这个项目中，我们总结了范式转变的数据。首先，我们证明 IPF 肺部 MPC（但不是对照肺 MPC）产生具有 IPF 成纤维细胞体外和体内特征的后代。接下来，我们表明，当原代肺成纤维细胞（IPF 或对照）与脱细胞肺 ECM（IPF 或对照）相互作用时： i) ECM 来源主要决定基因表达； ii) IPF肺ECM翻译激活ECM基因和编码其同源整合素受体的基因； iii) IPF肺ECM，但不是对照ECM，降低了成纤维细胞的miR29表达，miR29是ECM和增殖基因的有效负调节因子，创建了一个正反馈循环，为疾病的持续进展提供了分子机制。基于此，我们假设去细胞化IPF肺ECM将引导人肺MPC向IPF表型分化；并通过 miR29 表达的表观遗传调控来稳定该表型，从而创建一个正反馈环，驱动控制 IPF 成纤维细胞标志的基因。我们提出了两个具体目标来阐明分子机制。具体目标 1：IPF 成纤维细胞的起源 - 描述 MPC 在 IPF 肺 ECM 上获得 IPF 表型标志的机制。具体目标 2：疾病进展 - 剖析 IPF ECM 驱动的正反馈环路的分子和细胞机制，该环路增加整合素和 ECM 基因表达并抑制其负调节因子 miR29。如果我们实现了我们的目标，我们的工作将揭示 IPF 成纤维细胞及其病理 ECM 的发生、维持和增殖的机制。这些信息是开发针对 ECM（驱动 IPF 的间充质细胞相互作用）的疗法的基础。