The Altered DNA Methylome as a Determinant of Variable Disease Progression in IPF

DNA 甲基化组的改变是 IPF 疾病进展的决定因素

基本信息

批准号：
8903517
负责人：
STEVEN K HUANG
金额：
$ 43.62万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8903517
关键词：
Accounting Cells Cessation of life Characteristics Clinical Clinical Course of Disease Clinical Data Clinical Markers Complex DNA DNA Methylation DNA Methyltransferase DNA Modification Methylases Data Development Diagnosis Dinoprostone Disease Disease Progression Effector Cell Epigenetic Process Exhibits Fibroblasts Fibrosis Future Gene Expression Gene Expression Profile Genes Genetic Genomic DNA Goals Hamman-Rich syndrome Health Heterogeneity Impairment Incidence Individual Knowledge Lung Lung diseases Mediator of activation protein Methylation Mission Modeling Modification Molecular Molecular Profiling Natural History Nature Pathogenesis Pathway interactions Patients Pattern Production Public Health Publishing Relative (related person)Research Respiratory physiology Severity of illness Signal Transduction Technology Tissue-Specific Gene Expression Transforming Growth Factors United States United States National Institutes of Health Work clinical phenotype effective therapy epigenomics extracellular fibrogenesis genome-wide improved innovation insight knowledge base methylome next generation novel outcome forecast overexpression response therapeutic target transcriptomics treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with no known effective therapy. Despite the dismal median survival, the prognosis of individual patients is variable and unpredictable, with some patients remaining stable and others deteriorating rapidly. The mechanisms that account for the variability in patients' clinical disease course are unknown. Fibroblasts are the main effector cell in fibrosis, and their relentless and exuberant activity is felt to contribute to the progressive nature of IPF. IPF fibroblasts exhibit gene expression changes that persist in culture even after multiple cell passages, suggesting that epigenetic modifications may be responsible for some of these gene expression differences. Alterations in DNA methylation of select genes have been identified in IPF fibroblasts, but a global assessment of the DNA methylomic abnormalities in IPF and their contribution to disease progression has never been assessed. The objectives of this project are to explore how genome-wide DNA methylomic and transcriptomic changes in IPF cells contribute to the clinical variability in IPF and determine how specific anti- and profibrotic mediators, prostaglandin E2 (PGE2) and transforming growth factor (TGF)-�1 respectively, contribute to altered DNA methylation patterns in IPF. The central hypothesis is that fibroblasts of IPF patients acquire distinct alterations in the DNA methylome in response to multiple extracellular signals, and that these distinct patterns of methylation contribute to both the heterogeneous gene expression profiles of fibroblasts and variable rates of clinical progression in IPF patients. This project has two specific aims: 1) examine how DNA methylomic changes in IPF fibroblasts contribute to both variable fibroblast gene expression patterns and clinical disease progression, and 2) understand the mechanisms by which PGE2 and TGF-�1 regulate DNA methyltransferases (DNMTs) and DNA methylation patterns and how they may contribute to differences in DNA methylation and gene expression of IPF fibroblasts. Fibroblasts from IPF and nonfibrotic lungs will be examined for methylation differences using the Illumina HumanMethylation450 Bead-Chip Array. Differentially methylated genes will be correlated with differential gene expression and longitudinal clinical disease progression. In Aim 2, the effects o PGE2 and TGF-�1 on DNA methylation and DNA methylation machinery will be examined in normal and IPF fibroblasts. The approach is innovative because it will utilize nonbiased, "next-generation" technologies to correlate whole genomic DNA methylation patterns with longitudinal clinical data from IPF patients and delineate mechanisms that regulate DNA methylation machinery and specific DNA methylation patterns. This project is significant because it will establish DNA methylation as a mechanism that contributes to differential gene expression, altered fibroblast function, and ultimately clinical disease progression, offer insight into how DN methylation patterns may be regulated, and identify novel pathways that may be candidates for future therapeutic targeting.

描述（由申请人提供）：特发性肺纤维化（IPF）是一种毁灭性的肺部疾病，尚无有效的治疗方法，尽管中位生存率很低，但个体患者的预后是可变且不可预测的，一些患者保持稳定，而另一些患者则迅速恶化。解释患者临床变异的机制成纤维细胞是纤维化的主要效应细胞，其持续而旺盛的活性被认为有助于 IPF 的进行性，即使在多次细胞传代后，IPF 成纤维细胞也表现出持续存在的基因表达变化。修饰可能是 IPF 成纤维细胞中某些基因表达差异的原因，但对 IPF 中 DNA 甲基化异常的总体评估已被确定。该项目的目标是探索 IPF 细胞中全基因组 DNA 甲基组和转录组的变化如何影响 IPF 的临床变异，并确定特定的抗纤维化介质和促纤维化介质前列腺素 E2 如何发挥作用。 (PGE2) 和转化生长因子 (TGF)-1 分别导致 IPF 中 DNA 甲基化模式的改变。核心假设是，IPF 患者的成纤维细胞的 DNA 甲基化组发生了明显的变化。多种细胞外信号，并且这些不同的甲基化模式导致成纤维细胞的异质基因表达谱和 IPF 患者临床进展的不同速率。该项目有两个具体目标：1）检查 IPF 成纤维细胞中 DNA 甲基化的变化如何发挥作用。 2) 了解 PGE2 和 TGF-β1 调节 DNA 甲基转移酶 (DNMT) 和 DNA 的机制甲基化模式以及它们如何影响 IPF 成纤维细胞和非纤维化肺的成纤维细胞的甲基化差异，将使用 Illumina HumanMmethylation450 Bead-Chip Array 检测差异甲基化基因与差异基因表达的关系。在目标 2 中，PGE2 和 TGF-β1 对 DNA 甲基化和 DNA 的影响。该方法是创新的，因为它将利用无偏见的“下一代”技术将全基因组 DNA 甲基化模式与 IPF 患者的纵向临床数据关联起来，并描述调节 DNA 甲基化机制的机制。该项目意义重大，因为它将建立 DNA 甲基化作为一种机制，有助于基因表达差异、成纤维细胞功能改变以及最终临床疾病进展，从而深入了解 DN 的机制。甲基化模式可能受到调节，并确定可能成为未来治疗目标候选的新途径。