Pathologic Markers of Genetic Damage and Disease in IBD

描述(由申请人提供)： 这项申请是为了继续和扩展在加州大学旧金山分校(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。这项研究确定了活动性炎症性肠病(IBD)与遗传损伤之间的关系，特别是在克罗恩病(CD)的儿童患者中，并产生了遗传损伤生物标记物的初步证据，这些生物标记物可能标志着IBD儿童和青少年患癌症的易感性。在这些研究的过程中，在3个地点建立了患者招募、样本采集和样本处理的程序。基于上述科学和操作结果，隶属于儿童IBD联盟的另外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、麻省理工学院儿童医院和芝加哥大学儿童医院--已同意与加州大学旧金山分校、CHRCO和UCB合作继续这一项目。目前的R03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，以确定：(1)细胞遗传学损害与CD之间的关系；(2)细胞遗传学损害与疾病活动(儿科克罗恩病活动指数[PCDAI])或叶酸缺乏的关系；(3)亚甲基四氢叶酸还原酶(MTHFR)基因多态性与CD风险的相关性，b)细胞遗传学损害，以及c)叶酸、维生素B12和同型半胱氨酸水平。血液和口腔细胞样本将在每个合作中心收集，并运往UCB，使用标准化和经验证的方法进行处理。细胞遗传学损伤将通过采集患者和对照组口腔黏膜上皮细胞的微核分析，并与同一受试者淋巴细胞细胞遗传学损伤的血液学指标进行比较来评估。总之，拟议的项目旨在利用儿科炎症性肠病联合会独特的患者群体和UCB的专门实验室设施来阐明儿科IBD的发病机制、演变和预后。

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.