Translational control of the fibroblast phenotype in IPF

纤维化病变中的成纤维细胞对生长和生存信号表现出一种无法解释的自主性。 成纤维细胞至少有3个来源：循环、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 仍未定义。在这里，我们建议研究特发性肺患者的肺成纤维细胞。 并利用我们在癌症生物学方面的发现阐明自主功能的机制 导游。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elF4F。在癌细胞中，elF4F 通过选择性地将核糖体招募到组中，整合来自癌基因的生长和生存信号 授予自主性的抄本。我们的初步数据表明，elF4F的异常激活是一个 成纤维细胞中激活elF4F刺激细胞周期进入的特性 生长因子；基因工程小鼠缺乏elF4F的负调控因子 肺损伤的纤维化反应；在斑马鱼外胚层外植体中激活elF4F触发EMT。我们 因此，假设病理性翻译控制通过以下途径参与IPF的纤维化表型 调节EMT和增殖性自主的出现。检验这一假设的框架是 转录后操纵子理论认为，核糖体向信使核糖体的募集受 转录本5‘和3’非编码区中的调控元件。单独作用或与反式作用蛋白或 Micro RNA结合伙伴、RNA调控元件为核糖体募集提供指令。至 发现这些核糖体招募指令在IPF中可能会如何改变，我们提出了两个具体目标：1) 明确病理翻译调控与IPF成纤维细胞增殖自主性之间的联系机制；2) 检测肺泡上皮细胞EMT的翻译调控，并检测其与肺间质纤维化的相关性。我们的研究将 提供第一个系统水平的、全基因组的成纤维细胞表型检查 对其信使核糖核酸主动转化为蛋白质的定量检测。 相关性(请参阅说明)： 如果成功，我们的研究将准确地识别导致IPF的基因表达途径中的错乱 成纤维细胞的病理表型，并提供对EMT在成纤维细胞发生中的作用的洞察 这一信息有可能揭示新一类抗纤维化的分子靶点。 治疗和推出与疾病相关的新生物标记物进行临床试验。

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.