We propose to remain a Member of the Childhood Liver Disease Research and Education 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 to build a strong infrastructure to conduct patient-based studies on biliary atresia, cholestatic syndromes, mitochondrial hepatopathies and cystic fibrosis. Our key contributions included data submission and analysis of two retrospective studies;leadership in the development, implementation, and completion of the first clinical trial (the steroid trial); high enrollment and retention of subjects into prospective studies;completion of ancillary studies seeking novel molecular phenotypes of biliary atresia;completion of a pilot project on defects in bile acid synthesis;and participation in working groups and committees related to project reviews, writing of manuscripts, and development of core resources. We look forward to significantly contributing to the operation of ChiLDREN through three aims.
In Aim 1, we will enroll subjects into prospective ChiLDREN protocols to enable 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 have worked with Network investigators and NIDDK Program Directors to start a new trial for infants with biliary atresia (PRIME trial), and are completing the regulatory requirements to start a trial investigating the efficacy and safety of a small molecule inhibitor of the intestinal sodium-dependent bile acid transporter (IMAGINE-ITCH-INDIGO trial). We are also working in research groups to develop a trial to test a new fat-soluble vitamin preparation to treat vitamin deficiencies in cholestatic children with biliary atresia (CholADEK trial) and the use of glycerol-phenylbutyrate to treat cholestatic children with progressive familial intrahepatic cholestasis (PFIC). And in Aim 3, we will use state-of-the-art molecular techniques in ancillary studies using ChiLDREN data and tissue to discover biomarkers of disease phenotypes and treatment in biliary atresia, and to define genetic mutations in children with mitochondrial hepatopathies. By pursuing the three aims, we will be well positioned to fully execute the new Network aims of pursuing clinical science projects and conducting trials to improve the outcome of children with liver diseases.
We propose to become a member of the Childhood Liver Disease Research and Education Network (ChiLDREN) and to be a key contributor to the strong infrastructure to facilitate clinical sciences research and clinical trials in children with biliary atresia, cholestatic syndromes, mitochondrial hepatopathies, and cystic fibrosis. In addition, we will pursue ancillary studies to develop biomarkers of disease in biliary atresia and genetic basis of mitochondrial hepatopathies, and will seek to enroll subjects into innovative clinical trials to improve the outcome of children with liver diseases.
|Russo, Pierre; Magee, John C; Anders, Robert A et al. (2016) Key Histopathologic Features of Liver Biopsies That Distinguish Biliary Atresia From Other Causes of Infantile Cholestasis and Their Correlation With Outcome: A Multicenter Study. Am J Surg Pathol 40:1601-1615|
|Shneider, Benjamin L; Magee, John C; Karpen, Saul J et al. (2016) Total Serum Bilirubin within 3 Months of Hepatoportoenterostomy Predicts Short-Term Outcomes in Biliary Atresia. J Pediatr 170:211-7.e1-2|
|Wang, Kasper S; Tiao, Greg; Bass, Lee M et al. (2016) Analysis of surgical interruption of the enterohepatic circulation as a treatment for pediatric cholestasis. Hepatology :|
|Bezerra, Jorge A (2016) MDR3 mutation analysis: A step closer to precision medicine. Hepatology 63:1421-3|
|Asai, Akihiro; Miethke, Alexander; Bezerra, Jorge A (2015) Pathogenesis of biliary atresia: defining biology to understand clinical phenotypes. Nat Rev Gastroenterol Hepatol 12:342-52|
|Heubi, James E; Setchell, Kenneth D R; Jha, Pinky et al. (2015) Treatment of bile acid amidation defects with glycocholic acid. Hepatology 61:268-74|
|Ye, Wen; Rosenthal, Philip; Magee, John C et al. (2015) Factors Determining Î´-Bilirubin Levels in Infants With Biliary Atresia. J Pediatr Gastroenterol Nutr 60:659-63|
|Zhang, Wujuan; Jha, Pinky; Wolfe, Brian et al. (2015) Tandem mass spectrometric determination of atypical 3Î²-hydroxy-Î”5-bile acids in patients with 3Î²-hydroxy-Î”5-C27-steroid oxidoreductase deficiency: application to diagnosis and monitoring of bile acid therapeutic response. Clin Chem 61:955-63|
|Kamath, Binita M; Chen, Zhen; Romero, Rene et al. (2015) Quality of Life and Its Determinants in a Multicenter Cohort of Children with Alagille Syndrome. J Pediatr 167:390-6.e3|
|Teckman, Jeffrey H; Rosenthal, Philip; Abel, Robert et al. (2015) Baseline Analysis of a Young Î±-1-Antitrypsin Deficiency Liver Disease Cohort Reveals Frequent Portal Hypertension. J Pediatr Gastroenterol Nutr 61:94-101|
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