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Leveraging the epigenome of inflammatory bowel disease to gain mechanistic insights into disease pathophysiologyÃ¢ÂÂ

利用炎症性肠病的表观基因组来了解疾病病理生理学的机制

基本信息

批准号：
10018884
负责人：
SUBRA KUGATHASAN
金额：
$ 19.13万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-17 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10018884
关键词：
Accounting Adult Autoimmune Process Back Behavior Blood Characteristics Childhood Chronic Clinical Clinical Course of Disease Cohort Studies Colectomy Colitis Complex Crohn&apos s disease Cross-Sectional Studies DNA DNA Methylation Data Deposition Development Diagnosis Disease Disease Outcome Environmental Risk Factor Epigenetic Process Etiology Evolution Gene Expression Gene Expression Profile Genetic Genotype Inflammation Inflammatory Inflammatory Bowel Diseases Integration Host Factors Life Maintenance Therapy Maps Measures Medical Meta-Analysis Methylation Molecular Mucous Membrane Nature Onset of illness Operative Surgical Procedures Participant Pathogenesis Pathology Patients Phenotype Play Predisposition Process RNA Randomized Regulator Genes Relapse Reporting Research Personnel Role Severities Severity of illness Signal Transduction Site Subgroup Testing Therapeutic Time Tissue Sample Tissues Ulcerative Colitis Variant cohort disorder subtype epigenome experience follow-up genetic association genetic variant genome wide association study genome-wide healing inflammatory disease of the intestine insight longitudinal design methylation pattern methylome methylomics microbial microbiome molecular phenotype new therapeutic target patient stratification pediatric patients prevent prospective rectal risk variant transcriptome transcriptome sequencing transcriptomics

项目摘要

Contact PD/PI: Kugathasan, Subra PROJECT SUMMARY/ABSTRACT Ulcerative colitis (UC) is a chronic relapsing and remitting intestinal inflammatory disorder with a very heterogeneous clinical course. While on life-long maintenance therapy, although most patients achieve complete mucosal healing with no disease activity during the course of treatment of UC, a subgroup (~40%) experience chronically active severe disease with persistent inflammation as reflected by need for escalation of medical therapy or surgery. The reasons underlying such differential clinical course/disease severity are not well understood. Cross-sectional studies of DNA methylation, a key regulator of gene expression and molecular phenotype, have begun to reveal epigenetic associations with UC. However, owing to the dynamic plasticity of DNA methylation and UC disease behavior, it is critical to understand the temporal relationship between the methylome and the disease in order to establish the direction of causality and leverage the epigenome for therapeutic benefits. Here we hypothesize that, longitudinal framework – having DNA methylation data and well documented disease measures collected concurrently during the disease onset and at later time – supplemented by genetic association and the concept of Mendelian randomization, can help identify methylation changes that causally underlie disease pathology. Herein, using methylation data generated from DNA derived from the disease-relevant tissue, rectal mucosa, obtained at two time points – at diagnosis and 1 year follow-up – from participants in the PROTECT cohort, a pediatric prospective inception UC cohort, we plan to (i) identify DNA methylation changes that causally influence the development of UC, and modify its phenotypic expression and severity; and (ii) integrate these methylation data with prior genotype and gene expression data in order to elucidate the functional consequence of disrupted methylation patterns and to gain insights into molecular underpinnings of UC. In completion, the results of this project will provide new insights into the epigenetic basis of UC. Understanding the temporal relationship between how methylome changes during the course of the disease, as a result of varying clinical characteristics, and how disease subgroups evolve may aid in the identification of potentially causal epigenetic targets which could subsequently be leveraged for therapeutic benefits.

联系PD/PI: Kugathasan， Subra