In this application, the Principal and Co-investigators propose the development of a coordinated and integrated """"""""Rare Liver Disease Network"""""""" (RLDN) as a Rare Diseases Clinical Research Center in response to NIH RFA RR 03-008. The RLDN will focus on investigations of five genetic causes of intrahepatic cholestasis. These disorders have serious if not fatal consequences (without liver transplantation) and severely affect the child's normal growth and development. The five related disorders are alpha-1-antitrypsin deficiency, Alagille syndrome, progressive familial intrahepatic cholestasis (PFIC), bile acid synthesis and metabolism defects and mitochondrial hepatopathies. Each of these diseases is present in well below 200,000 Americans qualifying each as a rare disorder (orphan disease), and is both a clinically and scientifically important condition. This RLDN will be based out of The Children's Hospital in Denver and will be composed of the five following Clinical Sites within the United States, each with investigators who have extensive clinical care experience, patient populations and research programs for these disorders and each with a General Clinical Research Center: Children's Hospital of Philadelphia, Children's Hospital of Pittsburgh, Cincinnati's Children's Hospital, Mt. Sinai Hospital of New York City, and The Children's Hospital of the University of Colorado Health Sciences Center. The RLDN will develop a longitudinal hypothesis driven database study of these diseases. During this study, serum, DNA and liver tissue will be obtained on all patients and stored for future studies. The RLDN will also include three Biologic Core Facilities to ensure the highest quality analysis of genetic information, liver histopathology and bile acid biochemistry for subjects enrolled in this study; an Administrative Core; a Pilot/Demonstration Project program to encourage innovative scientific investigation; a Training Program in order to attract new investigators to the study of rare liver diseases; and development of electronic internet-based clinical, educational, histologic and research resources for these diseases. Input by support/advocacy groups for these rare liver disorders will be integrated into the Network at all levels. The RLDN will be a full partner in the Rare Diseases Clinical Research Network and will participate collaboratively with the other Clinical Research Centers and the Data and Technology Coordinating Center.
|Sokol, Ronald J (2010) Reloading against rare liver diseases. J Pediatr Gastroenterol Nutr 50:9-10|
|Heubi, James E; Setchell, Kenneth D R; Bove, Kevin E (2007) Inborn errors of bile acid metabolism. Semin Liver Dis 27:282-94|
|Sokol, Ronald J; Devereaux, Michael; Dahl, Rolf et al. (2006) ""Let there be bile""--understanding hepatic injury in cholestasis. J Pediatr Gastroenterol Nutr 43 Suppl 1:S4-9|
|McDaniell, Ryan; Warthen, Daniel M; Sanchez-Lara, Pedro A et al. (2006) NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet 79:169-73|
|Warthen, D M; Moore, E C; Kamath, B M et al. (2006) Jagged1 (JAG1) mutations in Alagille syndrome: increasing the mutation detection rate. Hum Mutat 27:436-43|
|Sokol, Ronald J; Mack, Cara L (2005) Optimizing outcomes and bridging biliary atresia into adulthood. Hepatology 41:231-3|
|Mack, Cara L; Sokol, Ronald J (2005) Unraveling the pathogenesis and etiology of biliary atresia. Pediatr Res 57:87R-94R|