Cholestatic 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, frequently necessitating liver transplantation. No single North American clinical center sees a large enough number of patients with these disorders to permit a rigorous approach to addressing 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 Baylor College of Medicine and Texas Children's Hospital (BCM/TCH) 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, a novel pilot and feasibility clinical trial applied to biliary atresia and a translational protocol focused on the pathogenesis of sclerosing cholangitis. The clinical center at BCM/TCH includes an outstanding group of clinician investigators with an extensive track record in synergistic translational and clinical research relevant to pediatric liver diseases. Performance to date in the on-going studies of ChiLDReN has been exemplary and has taken full advantage of a predominant market share of the population base of the Houston metropolitan region (5th largest in the United States) and the large referral patterns to TCH as a quaternary center for Pediatric Hepatology and Liver Transplantation. A pilot and feasibility trial of intravenous NAC will be conducted as an open label investigation in infants undergoing hepatoportoenterstomy for biliary atresia (IND 135796 and NCT03499249). The primary outcome measure will focus on biomarkers of bile flow. Promising findings in this pilot study could be expanded to a larger scale multi-center investigation as part of ChiLDReN. The proposed translational protocol will use metagenomic whole genome sequencing to assess the bacterial fecal microbiome in children with sclerosing cholangitis and correlate microbial signatures and bacterial gene expression patterns with clinical phenotypes characterized in the newly developed prospective observational study of primary sclerosing cholangitis in children.
Diseases in children 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 clinical center at Baylor College of Medicine and Texas Children's Hospital is ideally suited to participate in these prospective investigations and proposes investigations to improve outcomes in biliary atresia and understand the pathogenesis of sclerosing cholangitis.
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