We propose to develop a Biliary Atresia Clinical Center to perform translational research focused on diagnosis, pathogenesis, and novel therapeutic modalities for biliary atresia and neonatal hepatitis. These disorders are the main causes of neonatal cholestasis, with biliary atresia accounting for -50% of the indications for liver transplantation in children. The application is a logical extension of the long-standing mission of the applicant Center to provide exceptional care to any child with liver disease through comprehensive care and research. To pursue this mission, a clinical service focused exclusively on pediatric liver disease was created in 1985; since, then, we have served as a referral center for regional medical groups and institutions. We also performed clinical and patient-directed laboratory research to define specific causes of neonatal hepatitis and to explore novel therapeutic modalities for affected infants. Recently, we applied functional genomics to identify immunologic pathways that may regulate pathogenesis of biliary atresia. Despite these accomplishments, we recognize that further advances will depend directly on the access to a large patient population in a prospective manner for adequately powered studies. Therefore, we set two goals for the applicant Center: 1) to establish and maintain the infrastructure of a Clinical Center that will work in collaboration with other centers of the Biliary Atresia Clinical Research Consortium, and 2) to actively use the resources provided by the consortium to carry out studies on children with biliary atresia and neonatal hepatitis. To accomplish these goals, we propose an administrative structure jointly shared by medical and surgical faculty of the Center, a network of regional collaborators that will assure access to patients, and a database to gather clinical and laboratory information based on the natural history of biliary atresia. Using a model of translational research that is focused on the child with biliary atresia, we propose two studies to be carried with the approval by the Research Consortium. The first is a short-term study applying basic science technology to further defines the pathogenesis of this disease. The second is a 3-year open-label randomized study to establish the efficacy of corticosteroids in improving biliary flow following surgical portoenterostomy in infants with biliary atresia. Execution of these studies and access to a critical amount of clinical information and serum/tissues will facilitate research and generate hypotheses on pathogenesis and optimal treatment for children with biliary atresia and neonatal hepatitis.
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