Pathologic Markers of Genetic Damage and Disease in IBD

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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.