Circulating microRNA as a novel biomarker for inflammatory bowel disease

描述(由申请人提供)：本提案的目的是在儿科疾病诊断生物标志物的开发方面为申请人提供模范的转化性医学研究培训。为了实现这一目标，制定了炎症性肠病(IBD)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，会导致各种不适甚至危险的症状，包括腹泻、体重减轻、生长障碍、直肠出血、脓肿、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，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)。由于缺乏确凿的生物标志物，诊断和评估IBD的金标准是内窥镜/结肠镜检查，尽管这种侵入性和昂贵的操作与患者的风险有关。最近，具有诊断潜力的循环微RNA(MiRNA)图谱已被描述为几种疾病，包括癌症(3-8)。正如在初步研究中所描述的，我们已经确定了一组循环中的miRNAs，它们在CD中发生了显著变化。该提案的具体研究目标是：1)确定CD和UC特异的循环miRNA图谱，用作儿童IBD的诊断生物标记物；2)评估循环miRNAs作为儿童IBD预后预测因子和替代标记物的作用。血清将从费城儿童医院儿科IBD中心进行内窥镜/结肠镜检查的疑似IBD患者那里获得。IBD特异的miRNAs将通过微阵列进行鉴定，并在大的、独立的样本集中得到确认。将使用接收器工作特性分析将循环miRNAs的诊断潜力与当前的IBD生物标记物进行比较。将进行纵向研究，以确定循环miRNAs作为替代标记物和结果预测因子的有效性。除了研究目标外，还制定了一个全面的培训计划；该计划包括临床研究的课程以及关于生物标记物发现、微阵列分析和专业发展等主题的研讨会和会议。总体而言，拟议的培训方案平衡地介绍了成为一名成功的独立研究调查员所需的技能和经验，并可能大幅减少儿童IBD诊断和临床管理中对侵入性测试的需求。

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.