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转化医学研究培训。为了实现这一目标，已经制定了炎症性肠病（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，会导致各种不舒服甚至危险的症状，包括腹泻、体重减轻、生长衰竭、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）两种疾病类型，是影响儿童健康的最严重疾病之一；乳糜泻和UC的诊断高峰都发生在儿童时期（1,2）。由于缺乏结论性的生物标志物，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手术对患者有风险。最近，循环microRNA （miRNA）谱在包括癌症在内的几种疾病中具有诊断潜力（3-8）。正如初步研究中所述，我们已经确定了一组循环miRNA在CD中发生显著改变。该提案的具体研究目的是：1)确定CD和uc特异性循环miRNA谱，用于儿科IBD的诊断生物标志物；2)评估循环miRNA作为预后预测因子和儿科IBD替代标志物的用途。在费城儿童医院的儿科IBD中心，对疑似IBD进行内窥镜/结肠镜检查的患者进行血清采集。ibd特异性mirna将通过微阵列识别，并在大型独立样本集中进行确认。循环mirna的诊断潜力将通过受体工作特征分析与当前IBD生物标志物进行比较。将进行纵向研究，以确定循环mirna作为替代标记物和预后预测因子的效用。除了研究目标之外，还制定了一项全面的培训计划；该计划包括临床研究课程、研讨会和会议，主题包括生物标志物发现、微阵列分析和专业发展。总的来说，拟议的培训方案构成了成为一名成功的独立研究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大幅减少。

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.