Cholestatic liver disease remains a significant cause of morbidity and death in the pediatric population, yet little is known about the molecular processes that regulate intrahepatic bile duct growth and remodeling. Alagille syndrome (ALGS) is an autosomal dominant multi-system disorder caused by mutations in either the JAG1 or NOTCH2 genes and characterized by a paucity of bile ducts in the liver with resultant cholestasis. Despite the knowledge of the genes responsible for ALGS, there exists a wide phenotypic variability even within families with the same point mutations raising the possibility that modifier genes may play a role. Radical Fringe (Rfng) is a glycosyltransferase that modifies the Notch receptor and alters its affinity for its ligands. We have identified a phenotype of bile duct proliferation with an onset between two and three weeks of age in mice heterozygous for Jag1 and Rfng.
The aims proposed in this application seek to examine the changes in gene expression prior to this critical period of bile duct growth and remodeling. We will identify other potential targets of Rfng glycosylation and gene pathways involved in bile duct regulation. State-of-the-art laser capture microdissection will be employed to isolate RNA specifically from portal tracts. Collected samples will be run on the Affymetrix GeneChiph Mouse Gene 1.0 ST Array to evaluate for gene expression changes. In addition, the relationship between Notch2 and Rfng during bile duct remodeling will be examined using a novel mouse model haploinsufficient for Notch2 and Rfng. The goals of this application are to advance the investigation of the Jag1+/-Rfng+/- mutant mice and explore Notch pathway modifiers. Understanding the effect of glycosylation on the Notch receptor, subsequent downstream signaling and the involvement of alternate signaling pathways is vital for further insight into the hepatic phenotype in ALGS and potentially other biliary diseases. Ideally, the information gained from these experiments will lead to further insights into bile duct development, reveal new avenues for additional investigation and eventually lead to possible directed liver therapies for children and adults. )

Public Health Relevance

Cholestatic liver disease is a significant cause of morbidity and death in the pediatric population. The data gained from the proposed experiments will contribute to the understanding of bile duct growth and remodeling. This knowledge will ultimately lead to further insights into directed liver therapies for children and adults.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Research Grants (R03)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Podskalny, Judith M,
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Children's Hospital of Philadelphia
United States
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