Leveraging the epigenome of inflammatory bowel disease to gain mechanistic insights into disease pathophysiologyâÂÂ

联系PD/PI：Kugathasan，Subra 项目摘要/摘要 溃疡性结肠炎(UC)是一种慢性复发性和缓解性肠道炎症性疾病。 临床病程异质性。在接受终身维持治疗时，尽管大多数患者达到完全 UC治疗过程中无疾病活动的粘膜愈合：亚组(~40%)经验 慢性活动性严重疾病，伴有持续性炎症，反映为需要升级医疗服务 治疗或手术。这种不同的临床病程/疾病严重程度背后的原因不是很好。 明白了。DNA甲基化，基因表达和分子的关键调节因子的横断面研究 表型，已经开始揭示表观遗传学与UC的关联。然而，由于具有动态可塑性， DNA甲基化与UC疾病行为之间的时间关系至关重要 甲基组和疾病，以确定因果关系的方向并利用表观基因组 治疗方面的好处。在这里，我们假设，纵向框架-拥有DNA甲基化数据和 在疾病发作期间和以后同时收集的记录在案的疾病措施-补充 通过遗传关联和孟德尔随机化的概念，可以帮助识别甲基化变化 是疾病病理的因果基础。在这里，使用从来自于 疾病相关组织，直肠粘膜，在两个时间点--诊断时和1年随访时--从 在保护队列中的参与者，一个儿科预期开始UC队列，我们计划(I)鉴定DNA 甲基化改变导致UC的发生发展，并改变其表型表达和 严重性；和(Ii)将这些甲基化数据与先前的基因型和基因表达数据相结合，以便 阐明甲基化模式中断的功能后果并获得对分子的洞察 UC的基础。完成后，该项目的结果将为表观遗传学基础提供新的见解。 加州大学的。理解甲基化过程中甲基组变化之间的时间关系 疾病，作为不同临床特征的结果，以及疾病亚组如何演变，可能有助于 确定可随后用于治疗的潜在因果表观遗传靶点 福利。

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.