Translational control of the fibroblast phenotype in IPF

IPF 中成纤维细胞表型的转化控制

• 批准号: 8375051
• 负责人: Peter B Bitterman
• 金额: $ 47.79万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8375051
• 关键词: 3' Untranslated Regions; Alveolar; Binding; Binding Proteins; Biological; Biological Markers; Blood Circulation; Cancer Biology; Cell Cycle; Cell Proliferation; Cell division; Cells; Clinical Trials; Data; Differentiation and Growth; Disease; Ectoderm; Elements; Epithelial Cells; Excision; Fibroblasts; Frequencies; Gene Expression; Gene Expression Profile; Genes; Genetically Engineered Mouse; Growth; Growth Factor; Growth Factor Receptors; Hamman-Rich syndrome; Human; Instruction; Integrins; Kinetics; Lesion; Link; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Mediating; Messenger RNA; MicroRNAs; Molecular; Molecular Analysis; Molecular Target; Normal Cell; Oncogenes; Ontology; Operon; Pathway interactions; Patients; Pattern; Phenotype; Physiological; Process; Production; Property; Proteins; Publications; RNA; RNA Binding; Recruitment Activity; Refractory; Regulation; Regulatory Element; Report (document); Reporter; Ribosomes; Role; Sampling; Signal Transduction; Site; Source; Specimen; Structure of parenchyma of lung; System; Systems Biology; Testing; Tissues; Transcript; Translating; Translation Initiation; Translations; Zebrafish; base; cancer cell; epithelial to mesenchymal transition; genome-wide; insight; lung injury; malignant breast neoplasm; morphogens; prototype; response; theories

Fibroblasts populating fibrotic lesions manifest an unexplained autonomy for growth and survival signals. Fibrotic fibroblasts arise from at least 3 sources: the circulation, resident fibroblasts and the epithelial to mesenchymal transition (EMT). However, the connection between fibroblast origin and autonomous function remains undefined. Here we propose to study lung fibroblasts from patients with Idiopathic Pulmonary Fibrosis and elucidate the mechanism of autonomous function using our discoveries in cancer biology as a guide. In studies of human breast and lung cancer, we discovered that autonomy is conferred by pathological regulation of the translation initiation machinery, designated elF4F. In cancer cells, elF4F serves to integrate growth and survival signals from oncogenes by selectively recruiting ribosomes to groups of transcripts that confer autonomy. Our preliminary data indicate that aberrant activation of elF4F is a property of IFF fibroblasts; that activating elF4F in fibroblasts stimulates cell cycle entry in the absence of growth factors; that mice genetically engineered to lack negative regulators of elF4F have an exaggerated fibrotic response to lung injury; and that activating elF4F in zebrafish ectoderm explants triggers EMT. We therefore hypothesize that pathological translational control contributes to the fibrotic phenotype in IPF by mediating EMT and the emergence of proliferative autonomy. The framework for testing this hypothesis is the post transcriptional operon theory, which posits that recruitment of ribosomes to mRNA is governed by regulatory elements in the transcript 5' and 3' UTR. Acting alone or in concert with trans-acting protein or micro RNA binding partners, RNA regulatory elements provide the instructions for ribosome recruitment. To discover how these ribosome recruitment instructions might be altered in IPF, we propose 2 specific aims: 1) Define the mechanisms linking pathological translational control with IPF fibroblast proliferative autonomy; 2) Examine translational control of alveolar epithelial cell EMT and test its relevance to IPF. Our studies will provide the first systems level, genome-wide examination of the fibrotic fibroblast phenotype based on a quantitiative assesment of which mRNA are being actively translated into protein. RELEVANCE (See instructions): If successful, our studies will precisely identify derangements in the gene expression pathway that confer IPF fibroblasts with a pathological phenotype and provide insight into the role of EMT in the genesis of fibroblasts in the IPF lung.This information has the potential to reveal new classes of molecular targets for antifibrotic therapy and unveil new disease-relevant biomarkers for clinical trials.

纤维化病变的成纤维细胞表现出一种无法解释的生长和生存信号的自主性。 纤维化成纤维细胞至少有3个来源：循环系统、常驻成纤维细胞和上皮细胞。 间充质转化（EMT）。然而，成纤维细胞起源与自主功能之间的联系 仍然没有定义。在这里，我们建议研究特发性肺纤维化患者的肺成纤维细胞， 纤维化和阐明自主功能的机制，利用我们在癌症生物学方面的发现， 为着力在对人类乳腺癌和肺癌的研究中，我们发现自主性是由 翻译起始机制的病理调节，命名为eIF 4F。在癌细胞中，eIF 4F 通过选择性地将核糖体聚集到组中， 赋予自主权的抄本。我们的初步数据表明，eIF 4F的异常激活是一个重要因素。 IFF 4F的特性;在缺乏IFF 4F的情况下，激活成纤维细胞中的eIF 4F刺激细胞周期进入。 生长因子;基因工程改造缺乏elF 4F负调节因子的小鼠具有夸大的 对肺损伤的纤维化反应;以及激活斑马鱼外胚层外植体中的eIF 4F触发EMT。我们 因此，假设病理性翻译控制通过以下方式促成IPF的纤维化表型： 介导EMT和增殖自主性的出现。检验这一假设的框架是 转录后操纵子理论认为，核糖体向mRNA的募集受以下因素控制： 转录本5'和3' UTR中的调控元件。单独作用或与反式作用蛋白协同作用，或 微RNA结合伴侣，RNA调控元件提供核糖体募集的指令。到 发现这些核糖体募集指令在IPF中如何改变，我们提出了2个具体目标：1） 定义病理性翻译控制与IPF成纤维细胞增殖自主性之间的联系机制; 2） 检查肺泡上皮细胞EMT的翻译控制并检测其与IPF的相关性。我们的研究将 提供了第一个系统水平，全基因组检查的纤维化成纤维细胞表型的基础上， 定量评估mRNA被积极翻译成蛋白质。 相关性（参见说明）： 如果成功，我们的研究将精确地识别导致IPF的基因表达途径中的紊乱。 成纤维细胞与病理表型，并提供洞察EMT的作用，在成纤维细胞的发生 这些信息有可能揭示抗纤维化治疗的新的分子靶点。 并为临床试验揭示新的疾病相关生物标志物。