The role of C/EBP in pulmonary fibrosis

C/EBP在肺纤维化中的作用

• 批准号: 7680429
• 负责人: SEM H PHAN
• 金额: $ 34.21万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7680429
• 关键词: Acetylation; Affect; Alveolar; Animal Model; Apoptosis; Binding; Binding Proteins; Bleomycin; Bone Marrow; Bone Marrow Transplantation; CCAAT-Enhancer-Binding Protein-beta; CCAAT-Enhancer-Binding Proteins; Cells; Characteristics; Chimera organism; Chronic; Collagen Type I; Complex; Controlled Study; Data; Deposition; Development; Diagnostic; Elastin; Elements; Epithelial Cells; Equilibrium; Exhibits; Extracellular Matrix; Fibroblasts; Fibrosis; Gene Expression; Gene Targeting; Generations; Genes; Goals; Hamman-Rich syndrome; Human; In Vitro; Indium; Injury; Instruction; Knockout Mice; Lesion; Liver; Lung; Lung diseases; Mechanics; Mediating; Messenger RNA; Modeling; Modification; Mus; Myofibroblast; PTEN gene; Pathogenesis; Pathway interactions; Patients; Peptide Initiation Factors; Phenotype; Phosphorylation; Play; Post-Translational Protein Processing; Property; Protein Isoforms; Proteins; Pulmonary Fibrosis; Regulation; Reporter Genes; Role; Signal Transduction; Site; Smooth Muscle Actin Staining Method; Testing; Tissues; Translations; Undifferentiated; Wild Type Mouse; arginase; base; cell type; cytokine; effective therapy; human FRAP1 protein; in vivo; indium-bleomycin; inhibitor/antagonist; injured; insight; lung injury; new therapeutic target; outcome forecast; programs; promoter; response; synergism; transcription factor

Pathogenesis of progressive fibrotic lung diseases, such as idiopathic pulmonary fibrosis (IPF), remain poorly understood with many having no effective therapies. A key element in IPF is the presence of activated fibroblast phenotypes engaged in crosstalk with injured alveolar epithelial cells. Recently a key transcription factor, CCAAT enhancer binding protein p (C/EBPP) and its major isoforms, liver-enriched activator protein (LAP) and liver-enriched inhibitory protein (LIP), are found to be involved in regulation of myofibroblast differentiation, and critical for the development of pulmonary fibrosis in an animal model. However the regulatory mechanisms responsible for generation of the two isoforms, and their regulation of myofibroblast differentiation and pulmonary fibrosis remain to be elucidated. Two possible mechanisms for regulating LAP:LIP ratio have been proposed based on the control of different translation start sites by the translational initiation factor, elF4E and the CUG binding protein-1 (CUGBP-1), respectively. An additional mechanism is the use of an alternate transcriptional start site to generate the LIP isoform. While C/EBPp is known to regulate myofibroblast differentiation in vitro, additional mechanisms in vivo may be involved since this transcription factor is known to regulate other genes of potential relevance to fibrosis, including type I collagen, arginase I and elastin. Based on these previous findings, the central hypothesis of this project is that C/EBPp via its two key isoforms critically regulates myofibroblast differentiation and other target genes to promote and propagate pulmonary fibrosis. In common with the othre two projects, the focus is on elucidating the various fibroblast phenotypes that are central to IPF and the mechanisms of their genesis. The Specific Aims to test this hypothesis are to, 1) determine the mechanisms regulating C/EBPbeta isoform expression, 2) evaluate post-translational modification of C/EBPP and its significance in regulation of target gene expression, 3) investigate how C/EBPP regulates pulmonary fibrosis in vivo by use of C/EBPp knockout mice in bone marrow chimera studies, and 4) identify key C/EBPp target genes in vivo and in isolated lung fibroblasts. The upstream signaling and translational control studies have common elements with Projects 1 and 2, respectively, which should synergize the various projects. RELEVANCE (See instructions):

进行性纤维化肺疾病，如特发性肺纤维化（IPF）的发病机制仍然存在， 人们对此知之甚少，许多人没有有效的治疗方法。IPF的一个关键因素是 活化的成纤维细胞表型与受损的肺泡上皮细胞发生串扰。最近一把钥匙 转录因子CCAAT增强子结合蛋白p（C/EBPP）及其主要亚型，肝脏富集 激活蛋白（activator protein，EMPs）和肝脏富集抑制蛋白（liver-enriched inhibitory protein，LIP）参与了肝脏的免疫调节。 肌成纤维细胞分化，并且对于动物模型中肺纤维化的发展至关重要。 然而，负责产生两种异构体的调节机制，以及它们对 肌成纤维细胞分化和肺纤维化仍有待阐明。两种可能的机制 基于不同的翻译起始位点的控制，已经提出了调节翻译起始位点：LIP比率的方法。 翻译起始因子eIF 4 E和CUG结合蛋白-1（CUGBP-1）。额外 该机制是使用替代的转录起始位点来产生LIP同种型。当C/EBPP 已知在体外调节肌成纤维细胞分化，可能涉及另外的体内机制， 已知该转录因子调节与纤维化潜在相关的其它基因，包括I型 胶原蛋白、胶原酶I和弹性蛋白。基于这些先前的发现，该项目的中心假设是 C/EBPp通过其两个关键的同种型关键地调节肌成纤维细胞分化和其他靶基因， 促进和传播肺纤维化。与其他两个项目一样，重点是 阐明了对IPF至关重要的各种成纤维细胞表型及其发生机制。 检验这一假设的具体目的是：1）确定C/EBP β亚型的调节机制 2）评价C/EBPP的翻译后修饰及其在靶向调控中的意义 基因表达; 3）利用C/EBPP β在体研究C/EBPP β对肺纤维化的调控作用 在骨髓嵌合体研究中敲除小鼠，以及4）在体内和体内鉴定关键的C/EBPp靶基因。 分离的肺成纤维细胞。上游信号传导和翻译控制研究具有共同的要素 项目1和项目2将发挥协同作用。 相关性（参见说明）：