DNA Methylation Based Biomarkers and Epigenetic Regulation in IBS

IBS 中基于 DNA 甲基化的生物标志物和表观遗传调控

• 批准号: 8968752
• 负责人: Lin Chang
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8968752
• 关键词: Abdominal Pain; Address; Adult; Adverse effects; Affect; Animals; Autonomic nervous system; Behavioral; Biological; Biological Assay; Biological Markers; Biopsy; Brain; Chronic; Chronic Cancer Pain; Chronic Disease; Colon; Complex; Constipation; DNA Methylation; Data; Development; Diagnosis; Diagnostic; Diarrhea; Disease; Environmental Risk Factor; Epigenetic Process; Event; Exclusion; Failure; Flare; Functional Gastrointestinal Disorders; Functional disorder; GSTM1 gene; Gastroenterology; Gastrointestinal Diseases; Gastrointestinal tract structure; Gene Expression Profiling; Genes; Genetic Markers; Glutathione S-Transferase; Goals; Habits; High Prevalence; Hormones; Human; Individual; Intestines; Irritable Bowel Syndrome; Knowledge; Lead; Link; Measures; Mental disorders; Methylation; Molecular; Monitor; Mucous Membrane; Neuraxis; Neuropeptides; Ontology; Oxidative Stress; Pain; Pathogenesis; Pathway interactions; Patients; Pattern; Peripheral Blood Mononuclear Cell; Permeability; Play; Population; Prevalence; Primary Health Care; Recurrence; Role; Sampling; Sensitivity and Specificity; Sensory Disorders; Site; Stress; Symptoms; Techniques; Testing; Time; Tissues; Tubulin; United States; Woman; accurate diagnosis; base; bisulfite sequencing; cell motility; chronic abdominal pain; cohort; drug discovery; effective therapy; epigenetic marker; epigenetic regulation; gastrointestinal; gene environment interaction; gene function; genome wide methylation; genome-wide; histone modification; human RBX1 protein; human SNCAIP protein; hypothalamic-pituitary-adrenal axis; insight; methylation biomarker; methylation pattern; motor disorder; next generation; novel diagnostics; peptide hormone; polymerization; public health relevance; stressor; treatment response

 DESCRIPTION (provided by applicant): Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder that affects up to 15% of adults, predominantly women, in the United States. Symptoms include chronic or recurrent abdominal pain associated with diarrhea, constipation or both. It is considered a stress-sensitive disorder that is associated with altered brain-gut interactions. Biomarkers that can reliably diagnose IBS or monitor treatment response are currently lacking. The current proposal is based on our preliminary data that epigenetic markers, namely DNA methylation, can distinguish IBS patients from healthy individuals. DNA methylation is a key epigenetic mechanism that governs vertebrate gene function. It has emerged as a leading mechanism linking gene- environment interactions to long-term behavioral development, particularly in complex disorders such as IBS. Our preliminary data on genome-wide DNA methylation for peripheral blood mononuclear cells (PBMCs) in a limited number of subjects (IBS: N=12, healthy controls: N=12) identified a set of epigenetic markers located on genes including SSPO, RNF39, GSTM1, GSTM5, TPPP and SNCAIP that can potentially distinguish IBS patients from healthy controls. Gene ontology analysis showed an enrichment of genes involved in neuropeptide pathways. We validated the differential methylation of CpG sites in these genes using bisulphite sequencing. However, these findings need to be replicated and validated in a larger cohort. Therefore, the studies proposed here are intended to identify robust epigenetic biomarkers for an accurate diagnosis of IBS and to gain critical insights into the pathogenesis of this disorder. Our aims are to: 1) Identify DNA methylation based biomarkers using genome-wide DNA methylation profiling in peripheral blood mononuclear cells (PBMCs) in IBS. 2) Study genome-wide methylation and expression differences in colon tissue of IBS patients and HCs. In Aim 1, we will conduct a genome-wide DNA methylation profiling in a larger, independent cohort of IBS patients (N=108) and controls (N=36) replicate the differential methylation of selected markers in a subset of samples using an affordable technique (MethyLight PCR) that can be employed for the routine diagnosis of IBS. In Aim 2, we propose genome-wide DNA methylation and gene expression profiling of banked colonic mucosal biopsies collected from IBS patients (N=108) and controls (N=36) to investigate epigenetically deregulated genes and associated pathways, which can give important insights on pathophysiology of IBS.

 描述（由适用提供）：肠易激综合症（IBS）是一种慢性胃肠道疾病，在美国影响多达15％的成年人（主要是妇女）。症状包括与腹泻，便秘或两者相关的慢性或复发性腹痛。它被认为是一种与脑肠相互作用改变有关的应激敏感疾病。目前缺乏可以可靠地诊断IB或监测治疗反应的生物标志物。当前的建议基于我们的初步数据，即表观遗传标记，即DNA甲基化，可以将IBS患者与健康个体区分开。 DNA甲基化是控制脊椎动物基因功能的关键表观遗传机制。它已成为将基因环境相互作用与长期行为发展联系起来的主要机制，尤其是在复杂的IBS（例如IBS）中。我们在有限数量的受试者（IBS：n = 12，健康对照：n = 12）中，有关周围血液单核细胞（PBMC）的全基因组DNA甲基化的初步数据，确定了一组位于基因上的表观遗传标记，包括SSPO，RNF39，RNF39，GSTM1，GSTM1，GSTM1，GSTM5，TPP PPP和SNCAIPS，可以识别。基因本体分析表明，与神经肽途径有关的基因富集。我们使用双足石测序验证了这些基因中CpG位点的差异甲基化。但是，这些发现需要在较大的队列中复制和验证。因此，此处提出的研究旨在确定可靠的表观遗传生物标志物，以准确诊断IBS并获得对这种疾病发病机理的关键见解。我们的目的是：1）使用全基因组DNA甲基化分析在IBS中的外周血单核细胞（PBMC）中鉴定基于DNA甲基化的生物标志物。 2）研究IBS患者和HCS结肠组织中全基因组甲基化和表达差异。在AIM 1中，我们将在较大，独立的IBS患者（n = 108）中进行全基因组DNA甲基化分析，对照组（n = 36）在使用负担得起的技术（Methyllight PCR）中复制所选标记的差异甲基化，可用于常规IBS诊断IBS的常规诊断。在AIM 2中，我们提出了全基因组DNA甲基化和基因表达分析，对从IBS患者（n = 108）和对照组收集的库菌结肠粘膜活检和对照组（n = 36）进行了研究，以研究表观遗传导管的基因和相关途径，这可以给出对IBS病理生理学的重要见解。