Circulating microRNA as a novel biomarker for inflammatory bowel disease

描述（由申请人提供）：本提案的目的是为申请人提供儿科疾病诊断生物标志物开发方面的示范性转化医学研究培训。为实现这一目标，制定了炎症性肠病范围内的培训方案，包括研究目标和大量培训活动。IBD是一种以慢性炎症为特征的肠道疾病，导致各种不舒服甚至危险的症状，包括腹泻、体重减轻、生长障碍、直肠出血、腹泻、狭窄或瘘管。IBD包括克罗恩病（CD）和溃疡性结肠炎（UC）两种疾病类型，是影响儿童健康的最严重疾病之一; CD和UC的诊断高峰期都发生在儿童时期（1，2）。由于缺乏决定性的生物标志物，IBD诊断和评估的金标准是内窥镜/结肠镜检查，尽管这种侵入性和昂贵的程序与患者的风险相关。最近，已经描述了具有诊断潜力的循环microRNA（miRNA）谱用于几种病症，包括癌症（3-8）。如初步研究中所述，我们已经鉴定了一组在CD中显著改变的循环miRNA。该提案的具体研究目的是：1）鉴定CD和UC特异性循环miRNA谱，用作儿科IBD的诊断生物标志物; 2）评估循环miRNA作为儿科IBD结局预测因子和替代标志物的效用。血清将从费城儿童医院儿科IBD中心因疑似IBD进行内窥镜检查/结肠镜检查的患者中获得。IBD特异性miRNA将通过微阵列鉴定并在大的独立样本集中确认。将使用受试者操作特征分析将循环miRNA的诊断潜力与当前IBD生物标志物进行比较。将进行纵向研究以确定循环miRNA作为替代标志物和结果预测因子的效用。除了研究目标，一个全面的培训计划已经制定;该计划包括临床研究课程和研讨会和会议的主题，包括生物标志物发现，微阵列分析和专业发展。总体而言，拟议的培训方案构成了成为一名成功的独立研究者所需的技能和经验的平衡介绍，并可能导致在儿童IBD的诊断和临床管理中对侵入性检测的需求急剧减少。

DESCRIPTION (provided by applicant): The objective of this proposal is to provide the applicant with exemplary translational medical research training in the development of diagnostic biomarkers of pediatric disease. To achieve this objective, a training regimen within the scope of inflammatory bowel disease (IBD) had been developed, consisting of research aims and substantial training activities. IBD is an intestinal disorder characterized by chronic inflammation, resulting in a variety of uncomfortable and even dangerous symptoms including diarrhea, weight loss, growth failure, rectal bleeding, abscesses, strictures, or fistulas. IBD comprises two disease types, Crohn's disease (CD) and ulcerative colitis (UC), and is one of the most serious diseases affecting the health of children; the peak diagnosis period for both CD and UC occurs during childhood (1, 2). Due to a lack of conclusive biomarkers, the gold standard for diagnosis and evaluation of IBD is endoscopy/colonoscopy, although this invasive and costly procedure is associated with risks to the patient. Recently, circulating microRNA (miRNA) profiles with diagnostic potential have been described for several conditions, including cancer (3-8). As described in the Preliminary Studies, we have identified a set of circulating miRNAs that are significantly altered in CD. The specific research aims of the proposal are: 1) to identify CD- and UC-specific circulating miRNA profiles for use as diagnostic biomarkers of pediatric IBD and 2) to assess the utility of circulating miRNAs as predictors of outcome and surrogate markers of pediatric IBD. Sera will be obtained from patients presenting for endoscopy/colonoscopy for suspected IBD at the Pediatric IBD Center at the Children's Hospital of Philadelphia. IBD-specific miRNAs will be identified by microarray and confirmed in large, independent sample sets. The diagnostic potential of circulating miRNAs will be compared to current IBD biomarkers using receiver operating characteristic analysis. Longitudinal studies will be performed to determine the utility of circulating miRNAs as surrogate markers and predictors of outcome. In addition to the research aims, a comprehensive training program has been developed; this plan includes coursework in clinical research and seminars and conferences on topics including biomarker discovery, microarray analysis, and professional development. Overall, the proposed training regimen constitutes a balanced introduction to the skills and experience necessary to become a successful independent research investigator and may lead to a dramatic reduction in the need for invasive testing in the diagnosis and clinical management of IBD in children.