A novel telomerase expressing lung fibroblast phenotype

描述（由申请人提供）：广泛的长期目标是阐明端粒酶诱导在慢性纤维化肺疾病如间质性肺疾病、慢性阻塞性肺疾病（COPD）和哮喘的发病机制中的作用。已在肺损伤和纤维化的动物模型中观察到端粒酶的诱导，并且最近的证据指出端粒酶在人类中与端粒长度减少相关的某些类型的肺纤维化中的潜在作用。但端粒酶的确切作用，通常不表达或表达在成人体细胞中的低水平，仍然不清楚疾病的发病机制。也有越来越多的证据表明，端粒酶可能具有额外的功能意义，而不仅仅是维持端粒长度，包括调节细胞分化，基因表达和细胞存活/凋亡。在肺纤维化动物模型中诱导的表达端粒酶的成纤维细胞的起源尚不清楚，其发生的机制以及这种诱导的组织区室化或定位仍然是一个谜。该项目的中心假设是，在肺损伤和成纤维细胞纤维化中诱导端粒酶表达促进其存活，增加对凋亡的抵抗，从而促进纤维化。此外，假设这种表达端粒酶的成纤维细胞的潜在来源是骨髓，在那里它被来自受损肺的信号招募。为检验这一假设，提出了三个主要的具体目标：1）鉴定和表征在肺损伤和纤维化中具有诱导的端粒酶表达的骨髓细胞的表型，并确定该诱导的组织区室化，2）通过分析端粒酶基因表达的分子调控来确定端粒酶诱导和发生的机制，3）通过检测其对细胞存活、凋亡、基因表达和端粒长度维持的影响，分析这种诱导的端粒酶表达在肺纤维化中的作用。这将与阵列研究相结合，筛选和确定推定的端粒酶依赖性靶基因和转录因子，其中一些可能是在调节端粒酶表达本身的进口。了解端粒酶表达细胞的作用和起源应该为治疗进行性的并且通常具有致命结果的纤维化疾病提供额外的新的潜在靶点。公共卫生相关性：该研究项目将分析一种称为端粒酶的酶复合物在慢性纤维化肺病中的作用，例如在各种间质性肺病中，包括特发性肺纤维化。这种酶负责维持端粒的长度，端粒是染色体末端重复的DNA片段，但目前还不清楚为什么这种酶在患病的肺部高水平表达。该项目将试图阐明这种酶在纤维化肺病发展中的重要性，从而为目前缺乏有效治愈或治疗的许多疾病提供新的见解。希望研究目标的实现将为这些疾病的有效治疗和管理提供新的思路。

DESCRIPTION (provided by applicant): The broad long term objective is to elucidate the role of telomerase induction in pathogenesis of chronic fibrotic lung diseases, such as interstitial lung diseases, chronic obstructive pulmonary disease (COPD) and asthma. Induction of telomerase has been observed in animal models of lung injury and fibrosis, and recent evidence points to a potential role for telomerase in certain types of pulmonary fibrosis in humans related to reduced telomere length. But the precise role of telomerase, normally not expressed or expressed at low levels in adult somatic cells, remains unclear with respect to disease pathogenesis. There is also mounting evidence that telomerase may have additional functional significance beyond the mere maintenance of telomere length, including regulation of cell differentiation, gene expression and cell survival/apoptosis. The origin of the telomerase expressing fibroblast induced in animal models of pulmonary fibrosis is unclear and the mechanism underlying its genesis remains a mystery along with the tissue compartmentalization or localization of this induction. The central hypothesis of this project is that induction of telomerase expression in lung injury and fibrosis in fibroblasts promotes their survival with increased resistance to apoptosis and thus promotes fibrosis. Additionally it is hypothesized that a potential source of this telomerase expressing fibroblast is the bone marrow from where it is recruited by signals from the injured lung. Three major specific aims are proposed to test this hypothesis: 1) to identify and characterize the phenotype of the bone marrow-cells with induced telomerase expression in lung injury and fibrosis and determine the tissue compartmentalization of this induction, 2) to determine the mechanism of telomerase induction and genesis by analysis of the molecular regulation of telomerase gene expression, and 3) to analyze the role of this induced telomerase expression in pulmonary fibrosis by examination of its effects on cell survival, apoptosis, gene expression and telomere length maintenance. This will be combined with array studies to screen and identify putative telomerase-dependent target genes and transcription factors, some of which may be of import in regulating telomerase expression itself. Understanding the role and origin of the telomerase expressing cells should provide additional novel potential targets for therapy of fibrotic diseases that are progressive and often have a fatal outcome. PUBLIC HEALTH RELEVANCE: This research project will analyze the role of an enzyme complex called telomerase in chronic fibrotic lung diseases, such as in various interstitial lung diseases, including idiopathic pulmonary fibrosis. This enzyme is responsible for maintaining the length of telomeres, repeated pieces of DNA at the ends of chromosomes, but it is unknown why this enzyme is expressed at high levels in diseased lungs. This project will attempt to clarify the importance of this enzyme in the development of fibrotic lung disease and thus provide new insights into many of these diseases that currently lack an effective cure or therapy. It is hoped that attainment of the study's objectives will provide new ideas for effective treatment and management of these diseases.