Pediatric cholestatic and chronic liver diseases including Alagille syndrome, alpha-1 antitrypsin deficiency, bile acid synthesis defects, biliary atresia, cystic fibrosis, mitochondrial hepatopathies progressive familial intrahepatic cholestasis and primary sclerosing cholangitis, lead to significant morbidity and mortality in childhood and frequently necessitate liver transplantation. No single United States clinical center will care for enough 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 UPMC Children?s Hospital of Pittsburgh (CHP) 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 research infrastructure, 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 ChiLDReN studies 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. We propose a novel translational study utilizing human induced pluripotent stem cells coupled with ?liver on a chip? technology available at the University of Pittsburgh to individually characterize phenotypic variation in participants with. familial intrahepatic cholestasis 1 and 2 diseases. Also, abbreviated proposals will utilize existing ChiLDReN database and biosamples to demonstrate our unique capabilities to advance understanding of ChiLDReN diseases. A phase I/II pilot study to determine feasibility, tolerability, and safety of a FDA approved molecular chaperone to improve clinical (e.g. pruritus) and biochemical features associated with familial intrahepatic cholestasis 1 disease is also proposed.
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 is ideally suited to participate in these prospective investigations.
Showing the most recent 10 out of 23 publications
