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.