Integrin-Matrix Regulation of IPF Fibroblast Phenotype

IPF 成纤维细胞表型的整合素基质调节

• 批准号: 9099865
• 负责人: CRAIG A HENKE
• 金额: $ 45.85万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9099865
• 关键词: Adoptive Transfer; Alveolar; Alveolus; Asphyxia; Automobile Driving; Calcium-Binding Proteins; Cell Differentiation process; Cell Nucleus; Cell Proliferation; Cell physiology; Cells; Cessation of life; Cicatrix; Collagen; Complex; Cytometry; Cytoplasm; Deposition; Disease; Fibroblasts; Fibrosis; Gene Expression; HDAC4 gene; Hamman-Rich syndrome; Hypoxia; Immune; Integrins; Lung; Lung diseases; Maintenance; Mediating; Mesenchymal Stem Cells; Modeling; Mus; Nonmuscle Myosin Type IIA; Nuclear; Pathogenesis; Pathologic; Phenotype; Phosphoric Monoester Hydrolases; Population; Property; Protein Phosphatase 2A Regulatory Subunit PR53; Regulation; Role; Signal Pathway; Signal Transduction; Smooth Muscle Actin Staining Method; Stem cells; Structure; Structure of parenchyma of lung; TP53 gene; Testing; base; effective therapy; in vivo; migration; novel therapeutic intervention; programs; public health relevance; response; transcriptome sequencing

 DESCRIPTION (provided by applicant): Idiopathic Pulmonary Fibrosis (IPF) is a progressive, fatal fibrotic lung disease for which there is no effective therapy. IPF fibrotic progression is characterized by the relentless spread of fibrosis from scarred alveoli into normal adjacent alveolar units. Our studies indicate that there is a distinct IPF fibroblast phenotype characterize by aberrant integrin signaling leading to pathological activation of proliferation signaling pathways. We have discovered that IPF lung tissue harbors pathologic mesenchymal progenitor cells (MPCs) that are a cell-of-origin for IPF fibroblasts. Despite this discovery, the detailed mechanism(s) leading to the genesis and maintenance of IPF MPCs in the IPF lung and their differentiation to IPF fibroblasts remain unclear. We have found that IPF MPCs contain high levels of the calcium-binding protein S100A4 in the nucleus where it exists in a complex with histone deacetylase 4 (HDAC4). HDAC4 epigenetically regulates gene expression and has been implicated in stem cell and fibroblast differentiation. We have found that the S100A4/HDAC4 nuclear complex promotes IPF MPC propagation while suppressing differentiation. On the basis of these findings, we hypothesize that the S100A4/HDAC4 nuclear complex functions to maintain and promote the expansion of the IPF MPC population in the IPF lung. Recent studies have defined a critical role for a stiff fibrotic matrix in "programming" fibroblasts to acquire fibrotic properties and highlight the importance of the pathologic matrix as a driver of the progressive fibrosis in IPF. However, the role of the fibrotic matrix in directing PF MPC differentiation has not yet been examined. We hypothesize that a stiff fibrotic matrix directs IPF MPC differentiation to disease-mediating fibroblasts. This is based on exciting preliminary studies indicating that in response to interaction with a stiff matrix, the S100A4/HDAC4 nuclear complex becomes depleted and this is associated with IPF MPC differentiation. In the case of S100A4, contact with a stiff matrix promotes S100A4 translocation to the cytoplasm, where it associates with myosin IIA. The loss of nuclear HDAC4, triggered by contact with a stiff matrix, involves a decrease in the function of the a2 integrin/PP2A phosphatase axis. Our studies support a model where the S100A4/HDAC4 nuclear complex promotes IPF MPC proliferation and maintenance of IPF MPCs in the IPF lung. However, as fibrosis progresses IPF MPCs contact matrices of increasing degrees of stiffness. This triggers loss of the S100A4/HDAC4 nuclear complex and IPF MPC differentiation. We suggest that expansion of the IPF MPC population and subsequent differentiation fuels IPF fibrotic progression. To test our hypotheses we will: Aim 1: Determine the role of the S100A4/HDAC4 nuclear complex in regulating IPF MPC proliferation and suppression of differentiation. Aim 2: Analyze the role of matrix stiffness in regulating IPF MPC differentiation. Aim 3. Analyze the role of S100A4/HDAC4 in the ability of IPF MPCs to drive fibrotic progression in vivo employing the adoptive transfer model using immune-deficient mice.

 描述（由申请人提供）：特发性肺纤维化（IPF）是一种进行性、致命性的纤维化肺病，目前尚无有效的治疗方法。IPF 纤维化进展的特点是纤维化从疤痕肺泡持续扩散到正常的邻近肺泡单位。研究表明，存在一种独特的 IPF 成纤维细胞表型，其特征是异常的整合素信号传导导致增殖信号通路的病理激活。我们发现 IPF 肺组织。尽管有这一发现，但导致 IPF MPC 在 IPF 肺中发生和维持及其分化为 IPF 成纤维细胞的详细机制仍然存在。我们发现 IPF MPC 的细胞核中含有高水平的钙结合蛋白 S100A4，它与组蛋白脱乙酰酶形成复合物。 S100A4/HDAC4 核复合物可促进 IPF MPC 增殖，同时抑制分化。 S100A4/HDAC4 核复合物的功能是维持和促进 IPF 肺中 IPF MPC 群体的扩张。最近的研究已经确定了僵硬的关键作用。纤维化基质“编程”成纤维细胞以获得纤维化特性并强调病理基质的重要性 然而，纤维化基质在指导 PF MPC 分化中的作用尚未得到研究，我们发现僵硬的纤维化基质会指导 IPF MPC 分化为疾病介导的成纤维细胞。初步研究表明，在与刚性基质相互作用时，S100A4/HDAC4 核复合物会被耗尽，这与 IPF MPC 分化有关。 S100A4，与刚性基质接触会促进 S100A4 易位到细胞质，在细胞质中与肌球蛋白 IIA 结合。与刚性基质接触引发的核 HDAC4 损失涉及 a2 整联蛋白/PP2A 磷酸酶轴的功能下降。我们的研究支持一个模型，其中 S100A4/HDAC4 核复合物促进 IPF MPC 增殖和 IPF MPC 的维持然而，随着纤维化的进展，IPF MPC 接触基质的硬度增加，这会引发 S100A4/HDAC4 核复合物的丧失和 IPF MPC 的分化，我们认为 IPF MPC 群体的扩张和随后的分化会促进 IPF 纤维化的进展。测试我们的假设，我们将： 目标 1：确定 S100A4/HDAC4 核复合物在调节 IPF MPC 增殖和抑制分化中的作用。目标 2：分析基质硬度在调节 IPF MPC 分化中的作用。目标 3. 采用免疫缺陷小鼠的过继转移模型，分析 S100A4/HDAC4 在 IPF MPC 驱动体内纤维化进展的能力中的作用。