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.
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