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）是一种致命疾病，没有明确定义的病因。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。最近的数据表明在IPF中重新表达了发育基因特征。表观遗传调节，包括DNA甲基化和组蛋白的修饰，通常在发育过程中发生并响应衰老和环境刺激，从而导致基因表达的遗传变化与基因本身的任何变异无关。富含胞嘧啶 - 瓜氨酸（CPG岛）和组蛋白修饰的基因启动子区域的DNA甲基化均在基因沉默中起重要作用。这些范例在发育过程中对细胞分化很重要，并且对于许多癌症的肿瘤抑制剂沉默至关重要。表观遗传修饰可能是可逆的，因此具有吸引人的新疗法靶标。尽管越来越多的证据表明表观遗传调节可能在纤维化疾病中起重要作用，但很少有研究探讨了IPF中的表观遗传调节。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的成纤维细胞灶中不存在，它的缺失可能是由THY-1启动子区域的甲基化引起的，并且是可逆的。来自我们实验室的其他初步数据表明，已知在IPF中被下调的其他基因的表观遗传沉默。我们假设表观遗传变化改变了IPF中的基因表达谱，从而促进了纤维发生。这项研究将建立DNA甲基化作为IPF发病机理的重要因素，并为进一步探索这种致命疾病的表观遗传改变提供了支持，从而为发展新型治疗方法的发展奠定了基础。该提案将利用通过肺组织研究联盟（LTRC）获得的特征良好的组织的可用性来表征与慢性阻塞性肺疾病（COPD）相比，IPF中DNA甲基化的全球和基因特异性变化，以便将表观遗传学变化作为iPf中的重要病原体机制。该研究的目的将是：1。与COPD和对照肺组织相比，定义了DNA甲基化与IPF基因表达的关系，作者：a）a）在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，以及这些样品中的甲基化阵列分析，以及C）通过甲基化的基因确认甲基化基因通过甲基化PRCR；和2。测量IPF和COPD组织中全球DNA甲基化的区域变化，通过：a）定量分析和IHC抗甲基脊髓苷，b）分析DNA甲基发射酶（DNMTS）（DNMTS）和其他DNA甲基化的调节剂在局部组织水平上。这些研究将定义IPF中发生表观遗传学改变，特异性变化的表观遗传改变。这种重要且以前未开发的范式可能会对这种毁灭性疾病的发病机理产生明显的额外见解，并为IPF和其他纤维化疾病定义了新的治疗靶标。公共卫生相关性：特发性肺纤维化（IPF）是一种致命无法治愈的疾病，影响了100,000多名美国人，其原因是未知的，并且在肺部产生了渐进scar虫。在人类发育过程中，有一种生物学机制被称为表观遗传调节，越来越多地发现癌症和其他疾病异常。该项目将利用通过肺组织研究联盟（LTRC）获得的良好特征的IPF组织，以确定在IPF中看到的不受控制的疤痕的表观遗传异常的程度，从而为这种毁灭性疾病开发了新的治疗方法。 （抽象的结尾）