Clinical Center for Cholestatic Liver Disease in Children

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PROJECT SUMMARY/ABSTRACT We propose to remain a Member of the Childhood Liver Disease Research Network (ChiLDReN). As a Charter Member of the Network, our proposal represents a logical extension of the long-standing commitment of our Center to improve the care of children with chronic liver disease through innovative patient-based research. In the previous member of the Network, we worked collaboratively with investigators from other Centers and with the Data Coordinating Center to build a strong infrastructure to conduct patient-based studies on biliary atresia, cholestatic syndromes, mitochondrial hepatopathies and cystic fibrosis, with initial work to develop an observational and interventional protocol for children with primary sclerosing cholangitis (PSC). Our key contributions in the previous cycle included: 1) leadership and/or partnership in the development of network-wide clinical studies, with data analyses and publication of 11 original papers; 2) completion of the first two clinical trials (the steroid trial START and the IV-IG trial PRIME); 3) high enrollment and retention of subjects into prospective studies, including the new FORCE study; 4) timely processing of liver tissue by the staff of RNA Purification Service, Bile Acid Analysis Service, and Pathology Service to support Network studies; and 5) co-leading the organization of an NIH symposium on biliary atresia, with publication of its proceedings. We look forward to significantly contributing to the scientific goals and operational excellence of ChiLDReN through three aims. In Aim 1, we will enroll subjects into prospective ChiLDReN protocols to enable observational studies and translational science. This will be done by pursuing high enrollment rate of subjects into approved protocols, with the timely collection and submission of data and tissue samples to meet the enrollment goals established by the Network. In Aim 2, we will develop and implement research protocols for clinical trials. We are working with Network investigators to conduct a trial to determine the efficacy and safety of a small molecule inhibitor of the intestinal sodium-dependent bile acid transporter (IMAGINE-II trial) in children with cholestasis-associated pruritus. We are also developing a clinical trial to determine the efficacy of Vancomycin in children with PSC. And in Aim 3, we propose a new clinical trial focusing on the use of anti- oxidants to decrease biliary injury in infants who acquire biliary drainage after hepatoportoenterostomy for biliary atresia. We also propose an ancillary study to determine the role of matrix metalloproteinase-7 as a biomarker of hepatic fibrosis in biliary atresia. By pursuing the three aims, we will be well positioned to fully execute the new Network aims of pursuing translational science projects and conducting trials to improve the outcome of children with cholestatic liver diseases.