Pathologic Markers of Genetic Damage and Disease in IBD

IBD 遗传损伤和疾病的病理标志物

• 批准号: 6951873
• 负责人: MELVIN B. HEYMAN
• 金额: $ 12.32万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6951873
• 关键词: Crohn' s disease; biomarker; cancer risk; clinical research; cytogenetics; enzyme activity; folate; folate deficiency; genetic polymorphism; homocysteine; human subject; inflammatory bowel diseases; miscellaneous oxidoreductase; nutrition related tag; pediatrics; polymerase chain reaction; ulcerative colitis; vitamin B12

DESCRIPTION (provided by applicant): This application is for continuation and extension of pilot studies conducted at the University of California, San Francisco (UCSF), Children's Hospital & Research Center of Oakland (CHRCO), and the Children's Environmental Health Laboratory at the University of California at Berkeley (UCB). This investigation has identified a relationship between active inflammatory bowel disease (IBD) and genetic injury, particularly in pediatric patients with Crohn's Disease (CD), and has generated preliminary evidence of biomarkers of genetic injury that may signal susceptibility to cancer in children and adolescents with IBD. In the course of these studies, procedures were established for patient recruitment, sample collection, and specimen processing at the 3 sites. Based on the above scientific and operational results, 5 additional IBD centers associated within the Pediatric IBD Consortium - Texas Children's Hospital (Baylor), Children's Hospital of Philadelphia, Emory University, MassGeneral Hospital for Children, and the University of Chicago Children's Hospital - have agreed to collaborate with UCSF, CHRCO and UCB to continue this project. The present R03 proposal is to utilize the clinical resources of the 7 cooperating centers to prospectively provide the required number of newly diagnosed and untreated pediatric CD patients and matched controls to confirm: (1) the relationship between cytogenetic damage and CD; (2) the relationship of cytogenetic damage to disease activity (Pediatric Crohn's Disease Activity Index [PCDAI]) or folate deficiency; and (3) the correlation of methylenetetrahydrofolate reductase (MTHFR) polymorphisms with a) the risk of CD, b) cytogenetic damage, and c) folate, vitamin B12, and homocysteine levels. Blood and buccal cell specimens will be collected in each collaborating center and shipped to UCB for processing using standardized and validated methods. Cytogenetic damage will be assessed by micronucleus analysis of epithelial cells collected from buccal mucosa of patients and controls, and findings compared with hematological markers of cytogenetic injury in lymphocytes from the same subjects. In summary, the proposed project is designed to take advantage of the unique patient population of the Pediatric Inflammatory Bowel Disease Consortium and of the specialized laboratory facilities at UCB to elucidate the pathogenetic mechanisms, evolution, and prognosis of pediatric IBD.

描述（由申请人提供）： 本申请是为了继续和扩展在弗朗西斯科加州大学（UCSF）、奥克兰儿童医院和研究中心（CHRCO）以及加州大学伯克利分校（UCB）儿童环境健康实验室进行的试点研究。这项研究已经确定了活动性炎症性肠病（IBD）和遗传损伤之间的关系，特别是在克罗恩病（CD）的儿科患者中，并且已经产生了遗传损伤生物标志物的初步证据，这些生物标志物可能是IBD儿童和青少年对癌症易感性的信号。在这些研究过程中，在3个研究中心建立了患者招募、样本采集和标本处理程序。基于上述科学和操作结果，儿科IBD联盟内的另外5个IBD中心-德克萨斯儿童医院（贝勒），费城儿童医院，埃默里大学，马萨诸塞州儿童综合医院和芝加哥大学儿童医院-已同意与UCSF，CHRCO和UCB合作继续该项目。目前的R 03建议是利用7个合作中心的临床资源，前瞻性地提供所需数量的新诊断和未治疗的儿童CD患者和匹配的对照，以确认：（1）细胞遗传学损伤与CD之间的关系;（2）细胞遗传学损伤与疾病活动性之间的关系（儿童克罗恩病活动指数[PCDAI]）或叶酸缺乏;和（3）亚甲基四氢叶酸还原酶（MTHFR）多态性与a）CD风险，B）细胞遗传损伤，和c）叶酸、维生素B12和同型半胱氨酸水平的相关性。将在每个合作中心采集血液和口腔细胞标本，并运送至UCB，采用标准化和经验证的方法进行处理。将通过从患者和对照组颊粘膜采集的上皮细胞的微核分析评估细胞遗传学损伤，并将结果与来自相同受试者的淋巴细胞中细胞遗传学损伤的血液学标志物进行比较。总之，拟议的项目旨在利用儿科炎症性肠病联盟的独特患者人群和UCB的专业实验室设施来阐明儿科IBD的发病机制，演变和预后。