The creation of a multi-center collaborative consortium provides an unprecedented opportunity to improve the lives of children with neonatal liver disease. This Clinical Center application from four pediatric medical centers describes the collective clinical expertise, collaborative research experience, and outstanding institutional core facilities needed to be productive contributing members to this consortium. This application proposes participation in the consortium in three ways: 1. Clinical Data Collection: A uniform, concise data form and electronic collection system will be developed to manage clinical data. Relevant clinical data and tissue specimens will be contributed to the Consortium. The two research programs and four clinical programs collaborating in this proposal can contribute data from approximately 25 new patients with biliary atresia (BA)/year and 12 patients with neonatal hepatitis (NH)/yr. 2. Short-term study: Using available and accumulated specimens, we will study the pathogenesis, natural history, and clinical correlates of hepatic fibrogenesis in patients with biliary atresia and NH. A variation of the Knodell hepatic fibrosis scale will be used to determine the extent of hepatic fibrosis at the time of the Kasai procedure. Immunohistochemical and in situ hybridization techniques will be used to quantify the expression of specific molecular markers of hepatic fibrosis and inflammation. The severity of fibrosis or specific staining patterns will be correllated with patient diagnosis and response to the Kasai procedure. 3. Long-term study: To identify patterns of protein and gene expression that are unique to biliary atresia or that predict response to the Kasai procedure, gene expression profiles will be determined in wedge liver biopsies as well as in hepatocytes and biliary epithelial cells isolated by laser capture microdissection (LCM). Modern proteomic techniques will also be applied to serum samples to identify proteins synthesized and released by the injured liver. Similar to the genetic profile, the pattern of proteins will be correlated with clinical data to identify patterns of serum proteins that are disease specific or predict prognosis.
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