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):

进行性纤维化肺病，例如特发性肺纤维化（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 的一个关键要素是存在 激活的成纤维细胞表型与受损的肺泡上皮细胞发生串扰。最近有一个关键 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（LAP）和肝脏富集抑制蛋白（LIP）被发现参与调节 肌成纤维细胞分化，对于动物模型中肺纤维化的发展至关重要。 然而，负责产生两种亚型的调节机制及其对 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 根据不同翻译起始位点的控制，提出了调节 LAP:LIP 比率的建议。 分别是翻译起始因子 eF4E 和 CUG 结合蛋白-1 (CUGBP-1)。额外的 机制是使用替代转录起始位点来生成 LIP 同工型。虽然 C/EBPp 是 已知在体外调节肌成纤维细胞分化，体内可能涉及其他机制，因为 已知该转录因子可调节与纤维化潜在相关的其他基因，包括 I 型 胶原蛋白、精氨酸酶 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 通过其两个关键亚型严格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 阐明对 IPF 至关重要的各种成纤维细胞表型及其发生机制。 检验该假设的具体目标是，1) 确定调节 C/EBPbeta 亚型的机制 表达，2）评估C/EBPP的翻译后修饰及其在靶标调节中的意义 基因表达，3）研究C/EBPP如何利用C/EBPp在体内调节肺纤维化 在骨髓嵌合体研究中敲除小鼠，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要素 分别与项目 1 和 2 合作，这应该使各个项目产生协同作用。 相关性（参见说明）：