Cholestatic liver diseases are among the most important liver disorders that occur in infants and children, leading to devastating morbidity and accounting for over 70% of liver transplants performed during childhood, posing a major public health burden. In cholestasis, impairment of bile flow leads to the accumulation of hepatotoxic bile acids, cholesterol and other compounds that produce liver injury and complications such as pruritus and xanthomas;nutritional deficiencies caused by fat and fat-soluble vitamin malabsorption;and progressive hepatic fibrosis, portal hypertension and eventually chronic liver failure. Investigation of these disorders promises to advance scientific knowledge about liver development, pathophysiology and mechanisms of injury, as well as the discovery of biomarkers of disease and development and testing of new diagnostic and therapeutic strategies. A group of these disorders has been studied at our Center for the past 6 years within the Biliary Atresia Research Consortium (BARC) and the Cholestatic Liver Disease Consortium (CLiC), and include biliary atresia, idiopathic neonatal hepatitis, alpha- i-antitrypsin deficiency, Alagille syndrome, progressive familial intrahepatic cholestasis, bile acid synthesis defects, mitochondrial hepatopathies, and, most recently, cystic fibrosis liver disease. Members of our BARC and CLiC Clinical Centers at the University of Colorado Denver and The Children's Hospital have played major leadership roles as the Chair of the Steering Committee of BARC, the Principal Investigator and Chair of CLiC, and the Study Chair for the CFLD studies. The obiectives of this grant application are to become a Clinical Center and Administrative Core in the newly merged Childhood Liver Disease Research and Education Network;to continue to enroll participants and fully implement, complete and publish all of the ongoing BARC and CLiC study protocols, including the corticosteroid trial in biliary atresia;to participate in all new investigations, protocols and clinical trials initiated by the Network;to develop and propose new clinical studies and ancillary/pilot studies;to participate in training of research fellows and education of the public;to function as the Administrative Core of ChiLDREN;and to continue as one of the Genetic Cores and the Respiratory Chain Core. In this way, our Clinical Center will participate in the ChiLDREN goals of discovering new diagnostics, etiologies and treatment options for children with cholestatic liver diseases and to train the next generation of investigators in pediatric liver diseases. Relevance: This study will help to discover new diagnostic tests and treatments for children with liver disease and those who undergo liver transplantation. We will also train the researchers of the future who will study these rare diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZDK1-GRB-S (M1))
Program Officer
Sherker, Averell H
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University of Colorado Denver
Schools of Medicine
United States
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Mazariegos, George; Shneider, Benjamin; Burton, Barbara et al. (2014) Liver transplantation for pediatric metabolic disease. Mol Genet Metab 111:418-27
Ng, Vicky Lee; Haber, Barbara H; Magee, John C et al. (2014) Medical status of 219 children with biliary atresia surviving long-term with their native livers: results from a North American multicenter consortium. J Pediatr 165:539-546.e2
Menchise, Alexandra N; Mezoff, Ethan A; Lin, Tom K et al. (2014) Medical Management of Duodenum Inversum Presenting With Partial Proximal Intestinal Obstruction in a Pediatric Patient. J Pediatr Gastroenterol Nutr :
Sambrotta, Melissa; Strautnieks, Sandra; Papouli, Efterpi et al. (2014) Mutations in TJP2 cause progressive cholestatic liver disease. Nat Genet 46:326-8
Venkat, Veena L; Shneider, Benjamin L; Magee, John C et al. (2014) Total serum bilirubin predicts fat-soluble vitamin deficiency better than serum bile acids in infants with biliary atresia. J Pediatr Gastroenterol Nutr 59:702-7
Bezerra, Jorge A; Spino, Cathie; Magee, John C et al. (2014) Use of corticosteroids after hepatoportoenterostomy for bile drainage in infants with biliary atresia: the START randomized clinical trial. JAMA 311:1750-9
Sundaram, Shikha S; Alonso, Estella M; Haber, Barbara et al. (2013) Health related quality of life in patients with biliary atresia surviving with their native liver. J Pediatr 163:1052-7.e2
Feldman, Amy G; Sokol, Ronald J (2013) Neonatal Cholestasis. Neoreviews 14:
Molleston, Jean P; Sokol, Ronald J; Karnsakul, Wikrom et al. (2013) Evaluation of the child with suspected mitochondrial liver disease. J Pediatr Gastroenterol Nutr 57:269-76
Lee, Way Seah; Sokol, Ronald J (2013) Mitochondrial hepatopathies: advances in genetics, therapeutic approaches, and outcomes. J Pediatr 163:942-8

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