The role of C/EBP in pulmonary fibrosis

C/EBP在肺纤维化中的作用

• 批准号: 8242757
• 负责人: SEM H PHAN
• 金额: $ 38.97万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242757
• 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的发病机理，例如特发性肺纤维化（IPF） 没有有效疗法的许多人理解不足。 IPF的关键要素是存在 活化的成纤维细胞表型与受伤的肺泡上皮细胞进行串扰。最近一个钥匙 转录因子，CCAAT增强子结合蛋白P（C/EBPP）及其主要同工型，富含肝脏 活化剂蛋白（LAP）和富含肝的抑制蛋白（LIP）与调节有关 肌纤维细胞分化，对于动物模型中肺纤维化的发展至关重要。 但是，负责产生两种同工型的调节机制，其调节 肌纤维细胞分化和肺纤维化仍有待阐明。两个可能的机制 根据对不同翻译起始位点的控制，已经提出了调节膝盖：嘴唇比 转化起始因子ELF4E和CUG结合蛋白-1（CUGBP-1）。另一个 机制是使用替代转录起始位点生成唇部同工型。而C/EBPP是 已知可以在体外调节肌纤维细胞分化，因此可能涉及体内其他机制 已知该转录因子调节其他与纤维化的潜在相关性的基因，包括I型 胶原蛋白，精氨酸酶I和弹性蛋白。根据这些先前的发现，该项目的核心假设是 通过其两个键同工型进行C/EBPP严重调节肌纤维细胞分化和其他靶基因 促进和传播肺纤维化。与奥斯特尔两个项目共同，重点是 阐明对IPF及其起源机理核心的各种成纤维细胞表型。 检验该假设的具体目的是：1）确定调节C/EBPBETA同工型的机制 表达，2）评估C/EBPP的翻译后修饰及其在靶标调节中的重要性 基因表达，3）研究C/EBPP如何通过使用C/EBPP在体内调节肺纤维化 骨髓嵌合体研究中的敲除小鼠，4）在体内和在体内识别关键C/EBPP靶基因 孤立的肺成纤维细胞。上游信号传导和翻译控制研究具有共同的元素 分别将项目1和2分别协同化各种项目。 相关性（请参阅说明）：