Myofibroblasts in pulmonary fibrosis

肺纤维化中的肌成纤维细胞

• 批准号: 7591169
• 负责人: SEM H PHAN
• 金额: $ 37.36万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7591169
• 关键词: Actins; Adrenal Cortex Hormones; Affect; Alveolar; Apoptosis; Asthma; Autoimmune Diseases; Binding; Biological Process; CCAAT-Enhancer-Binding Proteins; Cell Differentiation process; Cell Survival; Cells; Characteristics; Chronic lung disease; Cicatrix; Classification; Collagen; Collagen Type I; Complex; DNA Methylation; Data; Deposition; Derivation procedure; Development; Diagnosis; Diagnostic; Differentiation Antigens; Disease; Ectopic Expression; Elements; Environmental Risk Factor; Epigenetic Process; Epithelial; Epithelial Cells; Extracellular Matrix; Fatal Outcome; Fibroblasts; Fibrosis; Gene Expression; Gene Targeting; Genes; Hamman-Rich syndrome; Histones; In Vitro; Indium; Inflammation; Inflammatory; Injury; Lesion; Lung; Lung diseases; Mediator of activation protein; Mesenchymal; Methylation; Myofibroblast; Pathogenesis; Pathologic; Patients; Phenotype; Prevalence; Process; Property; Protein Acetylation; Protein Isoforms; Proteins; Pulmonary Fibrosis; Regulation; Relative (related person); Respiratory Failure; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Signaling Pathway Gene; Smooth Muscle Actin Staining Method; Source; Staging; Steroids; Stimulus; Testing; Transact; Transcriptional Regulation; Work; base; cytokine; effective therapy; improved; inhibitor/antagonist; insight; interstitial; lung injury; new therapeutic target; novel; outcome forecast; promoter; response; response to injury; therapy outcome; transcription factor

DESCRIPTION (provided by applicant): Diverse injury to the lung from endogenous as well as environmental factors or agents may result in a stereotypic response leading to fibrosis and end stage lung disease with a potential fatal outcome. The long term objectives of this project are to determine the mechanisms underlying the genesis of the myofibroblast in lung injury and fibrosis, and to characterize the functional phenotype and roles of these cells in pulmonary fibrosis. The myofibroblast is a key source of mediators and extracellular matrix whose expression in fibrotic lesions is markedly stimulated. Fibrotic foci composed of myofibroblasts and other fibroblast phenotypes are diagnostic of idiopathic pulmonary fibrosis, a virtually fatal disease with no effective therapy. Hence understanding how these cells arise and the mechanisms regulating their survival may provide novel insight into the pathogenesis of pulmonary fibrosis. A number of mediators are known to induce myofibroblast differentiation in fibroblasts, however recent studies suggest additional derivation from epithelial cells through a process termed epithelial-mesenchymal transition (EMT). The central hypothesis of the proposal is that mediator induced genesis of the myofibroblast is dependent on regulation by transcription factors and their cognate elements in the alpha-smooth muscle actin ((-SMA) promoter, and that expression of (-SMA has consequences on elaboration of other key elements of the myofibroblast phenotype and concomitant loss of epithelial phenotype in EMT. To test this hypothesis, four specific aims are proposed. First, transcriptional regulation of myofibroblast differentiation will be analyzed from the standpoint of (-SMA gene expression. Second, epigenetic mechanisms involved in regulation of this differentiation will be investigated. Third, the functional role of (-SMA gene expression will be analyzed with respect to its effects on key signaling pathways, gene expression, and cell survival/apoptosis. The role of (-SMA in inducing the cellular phenotypic features of the myofibroblast will be identified by examining the effects of specific inhibitors of its expression and ectopic or induced expression in cells not usually known to express this actin isoform. Finally, the specific impact of induced (-SMA expression on EMT will be examined by analysis of the effects on cellular signaling and expression of epithelial marker genes. The proposed work should reveal novel insights to understanding processes associated with the multitude of diseases known to cause fibrosis. PROJECT NARRATIVE. The proposed studies attempt to uncover key biological processes that are important in the emergence of an activated fibroblast phenotype in fibrotic diseases of the lung, such as idiopathic pulmonary fibrosis and lung disease associated with autoimmune diseases such as rheumatoid arthritis. Thus the project is directly relevant to improving current understanding of these diseases, many of which such as idiopathic pulmonary fibrosis, have no current effective treatment and often result in chronic lung disease with a fatal outcome. Such fibrosis or scarring may also affect lung diseases with increasing prevalence, such as asthma. Improvement in understanding these processes will provide much needed insight into potentially novel treatments as well as approaches for management of patients with these diseases.

描述（由申请人提供）：内源性以及环境因素或药物对肺部的多种伤害可能导致刻板印象反应，导致纤维化和末期肺部疾病，并具有潜在的致命结果。该项目的长期目标是确定肺损伤和纤维化中成肌纤维细胞起源的机制，并表征这些细胞在肺纤维化中的功能表型和作用。肌纤维细胞是介质和细胞外基质的关键来源，其在纤维化病变中的表达受到明显刺激。由肌纤维细胞和其他成纤维细胞表型组成的纤维化灶是特发性肺纤维化的诊断，这实际上是致命的，没有有效的治疗。因此，了解这些细胞的产生方式以及调节其存活的机制可以为肺纤维化发病机理提供新的见解。已知许多介质可以诱导成纤维细胞中的肌纤维细胞分化，但是最近的研究表明，通过称为上皮 - 间质转变（EMT）的过程，来自上皮细胞的额外衍生物。该提案的核心假设是，介体诱导的成肌纤维细胞的生成取决于转录因子的调节及其在α-光滑肌肉肌动蛋白（（-sMA）启动子（ - SMA的表达）中，（-sMA的表达）的影响（-sMA都会影响（ - SMA）对这些肌肉词的其他关键元素的影响，并造成了EPESTY型和coscostial eptem epity epity epity epity epite and emertial emertial emertornty emeltem emeltemity emeltemity emeltemity emeltialt emeltialt emertialty emeltem的效果的影响。假设首先提出了四个具体目标，将从（-SMA基因表达。 （-sMA在诱导肌纤维细胞的细胞表型特征时，将通过检查其表达的特定抑制剂以及通常已知表达该肌动蛋白同工型的细胞中的特定抑制剂以及异位或诱导的表达的影响。 Finally, the specific impact of induced (-SMA expression on EMT will be examined by analysis of the effects on cellular signaling and expression of epithelial marker genes. The proposed work should reveal novel insights to understanding processes associated with the multitude of diseases known to cause fibrosis. PROJECT NARRATIVE. The proposed studies attempt to uncover key biological processes that are important in the emergence of an activated fibroblast phenotype in fibrotic diseases of the肺部，例如特发性肺纤维化和与自身免疫性疾病相关的肺部疾病，例如类风湿关节炎，因此该项目与当前对这些疾病的理解直接相关，其中许多疾病（例如，诸如特定性肺部纤维化）通常会导致当前有效的肺部疾病或与慢性疾病有关。患病率，例如哮喘。