Epigenetic Alterations in IPF Fibroblastic Foci

IPF 成纤维细胞灶的表观遗传改变

• 批准号: 7837607
• 负责人: Yan Sanders
• 金额: $ 7.33万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-11 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7837607
• 关键词: Affect; Age; Aging; American; Biological; Chronic Obstructive Airway Disease; Cicatrix; CpG Islands; Cytosine; DNA; DNA Methylation; DNA Methylation Regulation; DNA analysis; Data; Development; Developmental Gene; Disease; Epigenetic Process; Etiology; Fibroblasts; Gene Abnormality; Gene Expression; Gene Expression Microarray Analysis; Gene Expression Profile; Gene Silencing; Genes; Genomics; Guanine; Hamman-Rich syndrome; Human Development; Hypermethylation; Immunoprecipitation; Incidence; Lung; Malignant Neoplasms; Measures; Methylation; Modification; Pathogenesis; Phenotype; Play; Promoter Regions; Regulation; Research; Role; Sampling; Staging; Stimulus; Structure of parenchyma of lung; Tissues; Tumor Suppressor Proteins; Variant; abstracting; disorder control; fibrogenesis; histone modification; insight; new therapeutic target; novel; novel therapeutic intervention; promoter; public health relevance; response

DESCRIPTION (provided by applicant): Idiopathic Pulmonary Fibrosis (IPF) is a deadly disease without a clearly-defined etiology. Because the incidence increases with age, it is plausible that environmental effects may be important. Recent data indicate re-expression of developmental gene signatures in IPF. Epigenetic regulation, including DNA methylation and histone modification, which often occurs during development and in response to aging and environmental stimuli, results in heritable changes in gene expression independent of any variation in the genes themselves. DNA methylation at gene promoter regions rich in cytosine-guanine (CpG islands) and histone modifications both play important roles in gene silencing; these paradigms are important in cellular differentiation during development, and are critical in silencing of tumor suppressors in many cancers. Epigenetic modifications are potentially reversible and therefore attractive targets for development of novel therapies. Although there is increasing evidence that epigenetic regulation may play an important role in fibrotic disease, few studies have explored epigenetic regulation in IPF. Our lab has established that Thy-1, which suppresses the fibrotic phenotype of fibroblasts, is absent in fibroblastic foci of IPF, that its absence can be caused by methylation at the Thy-1 promoter region and is reversible. Additional preliminary data from our lab demonstrates epigenetic silencing of other genes known to be downregulated in IPF. We hypothesize that epigenetic changes alter the gene expression profile in IPF, promoting fibrogenesis. This study will establish DNA methylation as an important factor in the pathogenesis of IPF, and provide support for further exploration of epigenetic alterations in this deadly disease, thus setting the stage for development of novel therapeutic approaches. This proposal will leverage the availability of well-characterized tissues available through the Lung Tissue Research Consortium (LTRC) to characterize global and gene-specific alterations in DNA methylation in IPF in comparison to chronic obstructive pulmonary disease (COPD), in order to establish epigenetic alterations as an important pathogenic mechanism in IPF. The aims of the study will be to: 1. Define the relationship of DNA methylation to gene expression in IPF in comparison to COPD and control lung tissue, by: a) microarray analysis of gene expression in IPF, COPD, and control tissues, b) methylation array analysis in these samples, and c) confirmation of selected genes by methylation-specific PCR; and 2. Measure regional alterations of global DNA methylation in IPF and COPD tissues, by: a) quantitative analysis and IHC for anti-methylcytosine, and b) analysis of DNA methyltranserases (DNMTs) and other regulators of DNA methylation at the local tissue level. These studies will define the extent to which epigenetic alterations, specifically changes in DNA methylation, occur in IPF. This important and previously unexplored paradigm is likely to yield significant additional insight into the pathogenesis of this devastating disease, as well as to define novel therapeutic targets for IPF and other fibrotic disorders. PUBLIC HEALTH RELEVANCE: Idiopathic Pulmonary Fibrosis (IPF) is a deadly incurable disease affecting over 100,000 Americans, the cause of which is unknown, and which produces progressive scarring in the lungs. There is a biological mechanism for controlling expression of genes during human development known as epigenetic regulation, which is increasingly found to be abnormal in cancer and other diseases. This project will take advantage of the well characterized IPF tissues available through the Lung Tissue Research Consortium (LTRC) in order to determine the extent to which epigenetic abnormalities are responsible for the uncontrolled scarring seen in IPF, thus leading the way to development of novel therapies for this devastating disease. (End of Abstract)

描述（由申请人提供）： 特发性肺纤维化（IPF）是一种致命的疾病，没有明确的病因。由于发病率随着年龄的增长而增加，因此环境影响可能很重要。最近的数据表明 IPF 中发育基因特征的重新表达。表观遗传调控，包括 DNA 甲基化和组蛋白修饰，通常发生在发育过程中以及对衰老和环境刺激的反应，导致基因表达的可遗传变化，与基因本身的任何变化无关。富含胞嘧啶-鸟嘌呤（CpG 岛）的基因启动子区域的 DNA 甲基化和组蛋白修饰在基因沉默中都发挥着重要作用；这些范例对于发育过程中的细胞分化很重要，并且对于许多癌症中肿瘤抑制因子的沉默也至关重要。表观遗传修饰可能是可逆的，因此是开发新疗法的有吸引力的目标。尽管越来越多的证据表明表观遗传调控可能在纤维化疾病中发挥重要作用，但很少有研究探索 IPF 中的表观遗传调控。我们的实验室已经确定，抑制成纤维细胞纤维化表型的Thy-1在IPF的成纤维细胞病灶中不存在，其缺失可能是由Thy-1启动子区域的甲基化引起的，并且是可逆的。我们实验室的其他初步数据表明，已知在 IPF 中下调的其他基因存在表观遗传沉默。我们假设表观遗传变化改变了 IPF 的基因表达谱，促进纤维发生。这项研究将确定DNA甲基化是IPF发病机制中的一个重要因素，并为进一步探索这种致命疾病的表观遗传改变提供支持，从而为开发新的治疗方法奠定基础。该提案将利用肺组织研究联盟 (LTRC) 提供的充分表征的组织来表征 IPF 与慢性阻塞性肺疾病 (COPD) 中 DNA 甲基化的整体和基因特异性改变，以便建立表观遗传学模型改变是 IPF 的重要致病机制。该研究的目的是： 1. 与 COPD 和对照肺组织相比，通过以下方式确定 IPF 中 DNA 甲基化与基因表达的关系：a) IPF、COPD 和对照组织中基因表达的微阵列分析，b ) 这些样品中的甲基化阵列分析，以及 c) 通过甲基化特异性 PCR 确认所选基因； 2. 通过以下方式测量 IPF 和 COPD 组织中整体 DNA 甲基化的区域变化：a) 抗甲基胞嘧啶的定量分析和 IHC，以及 b) 局部组织水平 DNA 甲基转移酶 (DNMT) 和其他 DNA 甲基化调节因子的分析。这些研究将确定 IPF 中表观遗传改变（特别是 DNA 甲基化的变化）的程度。这一重要且先前未探索的范式可能会对这种破坏性疾病的发病机制产生重要的额外见解，并确定 IPF 和其他纤维化疾病的新治疗靶点。公共卫生相关性：特发性肺纤维化 (IPF) 是一种致命的无法治愈的疾病，影响着超过 100,000 名美国人，其原因尚不清楚，并且会在肺部产生进行性疤痕。在人类发育过程中，有一种控制基因表达的生物机制，称为表观遗传调控，越来越多的人发现这种机制在癌症和其他疾病中出现异常。该项目将利用肺组织研究联盟 (LTRC) 提供的特征明确的 IPF 组织，以确定表观遗传异常在多大程度上导致 IPF 中出现的不受控制的疤痕形成，从而为新型疗法的开发奠定基础。对于这种毁灭性的疾病。 （摘要完）