This proposal is in response to a request for applications for the Continuation of ChiLDReN, the Childhood Liver Disease Research Network. Over the past ten years, through a coordinated effort, investigations of eight cholestatic pediatri disorders have been advanced and we have established a robust database and biorepository for further research. Little is known about the pathogenesis, natural history, and optimal treatment strategies for the rare pediatric liver diseases investigated by ChiLDReN. We at The Children's Hospital of Philadelphia (CHOP) propose to continue to participate in this Consortium, and thereby advance the field through collaborative research. Only through collaboration can we improve the quality and efficiency of care provided to all individuals diagnosed with one of the diseases studied by this network. CHOP has been a highly productive member of ChiLDReN for the last 10 years. In this application, we propose to continue our participation in all aspects of the ChiLDReN consortium, including clinical trials, observational study protocols, dissemination of research findings and ancillary studies. We also propose to continue genetic screening of patients with Alagille Syndrome in the laboratory of Dr. Nancy Spinner. In addition, we have included a proposal for Genetics and Pathology services that we can offer to the Network. Biliary atresia (BA) is a progressive idiopathic, necroinflammatory disease of the extrahepatic biliary tree that presents in infancy, and accounts for 50% of all pediatric liver transplantations in the U.S. Currently there is no accurate way to predict outcome in children with BA at the time of diagnosis. A reliable algorithm for predicting clinical outcome would be valuable in defining prognosis and stratifying patients in clinical trials. In addition, improved understanding of the underlying molecular mechanisms would promote the development of novel therapies. In our scientific proposal, we will test the hypothesis that genomic and proteomic factors can predict outcome in BA. Using existing genotyping data from our group, we will conduct a genome wide association study of BA patients to identify significant single nucleotide polymorphisms and copy number variants that modify disease outcome. We will compare the variants detected in children with biliary atresia who survived with native liver beyond two years of age to those who did not. We also propose in depth studies to investigate the functional consequences of the variants identified in the GWAS. As a complementary strategy, we will use advanced proteomic technologies to identify serum proteins that predict clinical outcome in BA. Our study will leverage the extensive clinical and genomic data and biospecimens already collected by the ChiLDREN consortium to identify genetic modifiers and protein biomarkers that can predict outcome in this devastating disease. Our investigative team has the expertise and track record necessary to conduct these experiments. We anticipate that this work will contribute new knowledge about the biologic pathogenesis of BA and accelerate the pace of research into new treatments.

Public Health Relevance

With this application, The Children's Hospital of Philadelphia proposes to continue our participation in the ChiLDReN consortium, a group of 16 pediatric centers working together to study rare pediatric liver diseases. These diseases are important causes of suffering and death in children, but they are so rare that only by cooperating can we hope to improve outcomes for these children by performing large studies of new treatments. In addition, we propose to study genes and proteins that may predict the outcome of children affected with biliary atresia, the most common indication for liver transplantation in children.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZDK1-GRB-7 (M1))
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Sherker, Averell H
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Children's Hospital of Philadelphia
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Leonard, Laura D; Chao, Grace; Baker, Alastair et al. (2014) Clinical utility gene card for: Alagille Syndrome (ALGS). Eur J Hum Genet 22:
Ng, Vicky Lee; Haber, Barbara H; Magee, John C et al. (2014) Medical status of 219 children with biliary atresia surviving long-term with their native livers: results from a North American multicenter consortium. J Pediatr 165:539-546.e2
Tsai, Ellen A; Grochowski, Christopher M; Loomes, Kathleen M et al. (2014) Replication of a GWAS signal in a Caucasian population implicates ADD3 in susceptibility to biliary atresia. Hum Genet 133:235-43
Lin, Henry; Zoll, Bryan; Russo, Pierre et al. (2014) A challenging Case of Focal Extrahepatic Duct Obstruction/Hypoplasia in Alagille Syndrome. J Pediatr Gastroenterol Nutr :
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Russo, Pierre; Magee, John C; Boitnott, John et al. (2011) Design and validation of the biliary atresia research consortium histologic assessment system for cholestasis in infancy. Clin Gastroenterol Hepatol 9:357-362.e2
Leyva-Vega, Melissa; Gerfen, Jennifer; Thiel, Brian D et al. (2010) Genomic alterations in biliary atresia suggest region of potential disease susceptibility in 2q37.3. Am J Med Genet A 152A:886-95

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