Neonatal cholestatic liver diseases including Alagille syndrome, alpha-1 antitrypsin deficiency, bile acid synthesis defects, biliary atresia, cystic fibrosis, mitochondrial hepatopathies and progressive familial intrahepatic cholestasis, lead to significant morbidity and mortality in childhood, frequently necessitating liver transplantation. N single United States clinical center sees a large enough number of patients with these disorders to permit a rigorous answer to unresolved questions including etiology and pathogenesis, optimal methods of diagnosis and treatment, and factors that influence disease severity and prognosis. This competitive renewal proposal from the Pittsburgh Cholestatic Liver Disease Consortium at Children's Hospital of Pittsburgh of UPMC seeks to continue ongoing research activities in the Childhood Liver Disease Research Network (ChiLDReN). This application for renewal funding includes a strong commitment to continuing the on-going research efforts and two new proposals, one based upon the existing biosamples and clinical database, the other a novel clinical trial. The clinical center at CHP includes an outstanding group of clinician investigators with well-documented expertise in basic, translational and clinical investigation. Performance to date in the on-going studies of ChiLDReN has been exemplary and has taken full advantage of the population base within Western Pennsylvania and the unique referral patterns to CHP as a quaternary center for Pediatric Hepatology and Liver Transplantation. The existing biosample repository and clinical database will be analyzed using genome wide associate and Dynamic Bayesian Network analyses to identify genetic and immunologic factors that influence response to surgery for biliary atresia. An expanded access open label single armed study of the use of 4-phenylbutyrate in the treatment of progressive familial intrahepatic cholestasis (Byler Disease) is also proposed. The major end-points of this trial will be safety, tolerability and change in serum bile acids and other biochemical markers of liver disease.
Diseases in infants that impair the liver's ability to secrete bile (e.g. biliary atresia) are the leading indication for liver transplantation in childhood. Multi-centered prospective investigations are essential to improve the health of children afflicted by these disorders. The Pittsburgh Cholestatic Liver Disease Consortium at Children's Hospital of Pittsburgh of UPMC is ideally suited to participate in these prospective investigations and proposes investigations to analyze response to surgery in biliary atresia and to develop a novel therapy for a genetic form of liver disease.
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