A novel telomerase expressing lung fibroblast phenotype

表达肺成纤维细胞表型的新型端粒酶

• 批准号: 7247939
• 负责人: SEM H PHAN
• 金额: $ 35.33万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-05 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7247939
• 关键词: 5' Flanking Region; Adult; Animal Model; Apoptosis; Apoptotic; Bleomycin; Cell Proliferation; Cells; Characteristics; Cicatrix; Data; Development; Diagnostic; Elements; Evolution; Extracellular Matrix; Fibroblast Growth Factor 2; Fibroblasts; Fibrosis; Future; Gene Expression; Genes; Goals; Growth Factor; Hamman-Rich syndrome; Heterogeneity; In Vitro; Knockout Mice; Length; Lesion; Longevity; Lung; Lung diseases; Modeling; Myofibroblast; Nature; Numbers; Pathogenesis; Patients; Phenotype; Phosphotransferases; Population; Predisposition; Process; Property; Pulmonary Fibrosis; RNA; Rattus; Regulation; Role; Signal Pathway; Signal Transduction; Smooth Muscle Actin Staining Method; Source; Telomerase; Telomerase Inhibitor; Telomerase RNA Component; Telomerase inhibition; Telomere Length Maintenance; Testing; Transact; Transcriptional Regulation; Transforming Growth Factors; base; c-myc Genes; cytokine; in vivo; indium-bleomycin; injured; insight; lung injury; neoplastic cell; novel; novel strategies; novel therapeutics; promoter; response; size; telomerase reverse transcriptase; telomere; transcription factor

DESCRIPTION (provided by applicant): Increased numbers of fibroblasts are a key feature of pulmonary fibrosis, and their coalescence in densely populated cell formations, termed fibroblastic foci, is a diagnostic histopathological feature of idiopathic pulmonary fibrosis (IPF). Increased proliferation is a likely mechanism for this increase in fibroblasts whose phenotype is distinct from cells isolated from normal lung. Interestingly a new fibroblast phenotype is found to emerge in animal models of lung injury and fibrosis characterized by the expression of telomerase activity. While telomerase activity is associated with increased proliferative capacity and life span in certain cells during early development and many tumor cells, its significance in the pathogenesis of pulmonary fibrosis is unknown. In this project it is hypothesized that emergence de novo of a telomerase-expressing fibroblast phenotype is induced by certain factors resulting in increased cell proliferation and/or survival. This would increase the pool size of proliferative cells serving as an intermediate differentiated population that can terminally differentiate to the myofibroblast phenotype. Four specific aims are proposed to test this hypothesis. First, the mechanism of telomerase induction will be studied in lung fibroblasts. The telomerase gene and its 5'-flanking sequences will be cloned for analysis of transcriptional regulation. Second, the relationship between the telomerase expressing and myofibroblast phenotypes will be examined by analyzing the relationship between telomerase and (-smooth muscle actin gene expression, and whether the transcriptional regulatory mechanisms for both genes are somehow related in a functionally meaningful way in terms of cellular differentiation. Third, the functional significance of telomerase expression will be analyzed by comparing telomere length with telomerase expression in vivo and in vitro, and whether telomerase expression endow cells with differential characteristics with respect to response to growth factors and/or apoptotic signals. Finally, the role of telomerase in pulmonary fibrosis will be examined in vivo in the bleomycin model by use of telomerase (either telomerase reverse transcriptase or telomerase RNA component) knockout mice as well as specific telomerase inhibitors. By using these combined approaches, new insights into the potential role and significance of this telomerase expressing phenotype will be uncovered, which may prove to be useful for devising future novel therapeutic approaches.

描述（由申请人提供）：成纤维细胞的数量增加是肺纤维化的关键特征，它们在人口稠密的细胞形成中合并为成纤维细胞灶，是特发性肺纤维化（IPF）的诊断组织病理学特征。增加增殖是这种增加的成纤维细胞增加的机制，其表型与从正常肺部分离的细胞不同。有趣的是，在肺损伤的动物模型和纤维化模型中发现了一种新的成纤维细胞表型，其特征是端粒酶活性的表达。虽然端粒酶活性与早期发育和许多肿瘤细胞的某些细胞的增殖能力和寿命增加有关，但其在肺纤维化发病机理中的重要性尚不清楚。在这个项目中，假设表达端粒酶表达成纤维细胞表型的从头出现是由某些因素引起的，从而导致细胞增殖和/或存活增加。这将增加可以用作中间分化群体的增殖细胞的池大小，该细胞可以与肌成纤维细胞表型最终区分。提出了四个特定目标来检验这一假设。首先，将在肺成纤维细胞中研究端粒酶诱导的机制。端粒酶基因及其5'Fancing序列将被克隆以分析转录调节。其次，将通过分析端粒酶和（ - 光滑肌肉肌动蛋白基因表达表达，以及两个基因的转录调节机制之间的关系是否在功能上有意义的方式中，远程远程分析远期的远距离，远程分析的远程相关的方式，将检查端粒酶与转录调节机制是否在远程远程方面相关。在体内和体外表达，以及端粒酶表达的endow特征在对生长因子和/或凋亡信号的反应方面是否存在，端粒酶在肺纤维化中的作用将在体内通过使用telemerase模型在体内（使用催化型反式telemerase reversexompase and telomase telomase antose telemase antose temose telomase commentase Recone）在体内检查通过使用这些联合方法，将发现对表达表型的潜在作用和意义的新见解，这可能被证明可用于设计未来的新型治疗方法。