Role of Infectious Agents in Pediatric Crohn's Disease

传染源在小儿克罗恩病中的作用

• 批准号: 6824565
• 负责人: BENJAMIN David GOLD
• 金额: $ 12.91万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6824565
• 关键词: Crohn' s disease; age difference; biopsy; clinical research; communicable diseases; disease /disorder etiology; endoscopy; gastrointestinal imaging /visualization; gene expression; genetic susceptibility; human subject; immunocytochemistry; in situ hybridization; inflammatory bowel diseases; microarray technology; pediatrics; polymerase chain reaction

This R03 proposal will develop and standardize an appropriate clinical and laboratory approach to investigating potential infectious etiologies of pediatric Crohn's disease (CD). We aim to standardize specimen procurement, processing and testing with unique, validated laboratory assays to detect select infectious agents in pediatric intestinal biopsies, and evaluate the appropriateness of different control specimens. Future studies to test whether infection(s) cause pediatric CD or determine its morbidity demand these tools and methods. CD pathobiology is unclear. It has been proposed that one or more infectious agents precipitate CD in a genetically susceptible host and it may be easier to identify some agents in childhood CD. Current scientific evidence does not prove causality, despite research on a number of specific microbes (e.g., enteroadherent Escherichiae coli, measles virus). To test infectious hypotheses, valid diagnostic tools must be developed and tested in well-characterized cohorts of children as well as adults employing uniform case and control definitions. Differences between childhood and adult onset CD might signify risk factor differences: children can have more severe intestinal disease, increased risk of colon cancer and earlier complication onset. Children, particularly with new onset disease, may represent a unique population to study environmental factors (e.g., infection), since younger age brings shorter and less complicated exposure histories to confound analyses. The Pediatric IBD Consortium of 6 large, geographically diverse U.S. centers represents an excellent platform to investigate potential infectious triggers of CD, evaluating and recording clinical and epidemiologic data on approximately 288 newly diagnosed pediatric CD cases per year in a comprehensive database. Our application proposes that adequate collection of intestinal biopsies from uniformly-defined Consortium cases and controls and validation of sensitive and specific laboratory tools to detect potential infectious triggers of CD in such specimens can be achieved. Our R03 aims to: 1) standardize collection (e.g., anatomic source), processing and banking of gastrointestinal biopsies obtained during clinically-indicated endoscopy of well-characterized children with CD and well-characterized controls; 2) define, standardize and verify "appropriate" controls, "non-diseased" biopsies from cases vs. clinically-indicated biopsies from children without IBD (e.g., Hirschsprung's disease); 3) standardize and validate detection of certain infectious agents in these specimens through pathology-based (IHC, ISH), broad-range amplification-based (PCR) and organism-specific (e.g., MAP) molecular analysis complemeted by culture for MAP and localization of pathogens within diseased tissue. Parallel comparisons of intestinal biopsies to gene arrays on stool specimes from cases and controls to ascertain the role of indigenous colonic microflora will also be performed. Subsequent prospective application of methods and systems developed by this proposal to the uniquely large, well characterized Consortium cohort will optimize detecting differences between CD and non-disease.

本R 03提案将制定并标准化适当的临床和实验室方法，以调查儿科克罗恩病（CD）的潜在感染病因。我们的目标是通过独特的、经验证的实验室检测来标准化标本的采集、处理和检测，以检测儿科肠道活检中的选定感染因子，并评估不同对照标本的适当性。未来的研究将测试感染是否 引起儿童CD或确定其发病率需要这些工具和方法。CD病理学尚不清楚。有人提出，一种或多种传染性因子在遗传易感宿主中沉淀CD，并且可能更容易识别儿童CD中的某些因子。目前的科学证据并不能证明因果关系，尽管对一些特定的微生物进行了研究（例如，肠粘附性大肠杆菌、麻疹病毒）。为了验证传染性假说， 必须采用统一的病例和对照定义，开发有效的诊断工具，并在特征明确的儿童和成人队列中进行测试。儿童和成人发病CD之间的差异可能意味着风险因素的差异：儿童可能有更严重的肠道疾病，结肠癌的风险增加和早期并发症发作。儿童，特别是新发疾病的儿童，可能是研究环境因素的独特人群（例如，感染），因为年龄越小，暴露史越短， 混淆分析。儿科IBD联盟由6个大型的、地理位置多样化的美国中心组成，是一个研究CD潜在感染触发因素的绝佳平台，在一个综合数据库中评估和记录每年约288例新诊断的儿科CD病例的临床和流行病学数据。我们的申请提出，从统一定义的财团病例和对照中充分收集肠道活检， 可以实现检测这些样本中CD的潜在传染性触发物的灵敏和特异的实验室工具。我们的R 03旨在：1）标准化收集（例如，解剖学来源），处理和储存在具有良好特征的CD儿童和具有良好特征的对照组的临床适应症内镜检查期间获得的胃肠道活检; 2)定义、标准化和验证“适当的”对照，来自病例的“非病变”活检与来自无IBD儿童的临床指示活检（例如，先天性巨结肠）; 3）通过基于病理学（IHC，ISH）、基于宽范围扩增（PCR）和生物体特异性（例如，MAP）分子分析，辅之以MAP培养和病原体定位 在病变组织中。还将对病例和对照组的肠道活检与粪便标本的基因阵列进行平行比较，以确定土著结肠微生物菌群的作用。随后将本提案开发的方法和系统前瞻性应用于独特的大型、良好表征的联盟队列，将优化CD和非疾病之间的差异检测。