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（由适用提供）：特发性肺纤维化（IPF）是一种进行性致命的纤维化肺部疾病，没有有效的治疗。 IPF纤维化进展的特征是从疤痕肺泡中纤维化不断扩散到正常的相邻肺泡单元。我们的研究表明，存在一个独特的IPF成纤维细胞表型，其特征是整联蛋白信号传导导致增殖信号通路的病理激活。我们发现，IPF肺组织具有病理间充质祖细胞（MPC），是IPF成纤维细胞的原始细胞。尽管发现了这一发现，但详细的机制导致IPF肺中IPF MPC的起源和维持，并且它们与IPF成纤维细胞的分化尚不清楚。我们发现，IPF MPC在其与组蛋白脱乙酰基酶4（HDAC4）中存在的核中包含高水平的钙结合蛋白S100A4。 HDAC4表观遗传调节基因表达，并已在干细胞和成纤维细胞分化中实施。我们发现S100A4/HDAC4核复合物在抑制分化的同时促进IPF MPC传播。根据这些发现，我们假设S100A4/HDAC4核复合物的功能是维持和促进IPF肺中IPF MPC人群扩张的扩展。最近的研究定义了刚性纤维化基质在“编程”成纤维细胞中获得纤维化特性的关键作用，并突出了病理基质的重要性 IPF进行性纤维化的驱动力。但是，尚未研究纤维化基质在指导PF MPC分化中的作用。我们假设僵硬的纤维化基质将IPF MPC分化引导为疾病中的成纤维细胞。这是基于令人兴奋的初步研究，表明在与刚性基质的相互作用时，S100A4/HDAC4核复合物已加深，这与IPF MPC分化有关。在S100A4的情况下，与刚性基质接触会促进S100A4转移到细胞质，并与肌球蛋白IIA相关。与刚性基质接触触发的核HDAC4的丧失涉及A2整合素/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肺中IPF MPC的IPF MPC增殖和维持。然而，随着纤维化的发展，IPF MPC的接触材料的刚度增加。这触发了S100A4/HDAC4核复合物和IPF MPC分化的损失。我们建议扩大IPF MPC种群和随后的分化燃料IPF纤维化进展。为了检验我们的假设，我们将：目标1：确定S100A4/HDAC4核复合物在调节IPF MPC增殖和抑制分化方面的作用。 AIM 2：分析基质刚度在确定IPF MPC分化中的作用。 AIM 3。分析S100A4/HDAC4在使用免疫缺陷型小鼠使用自适应转移模型的体内驱动纤维化进展能力的能力中的作用。