The Biesecker Pediatric Liver Center at The Children’s Hospital of Philadelphia is actively involved in research studies on liver and bile duct disease and development. Our research group is working to understand the molecular basis of normal and abnormal bile duct development in humans.
The group consists of a collaborative and interactive group of labs, working in different organisms. The research labs study the biology of human disease states, work on mouse models to define and analyze genes important in bile duct development, and work in the zebrafish model to identify genes important in bile duct development and understand their functioning.
One of the areas of interest for the bile duct development group is the role of Notch signaling in bile duct and liver development. This work illustrates the power of the constellation of investigators in our group. The Notch Signaling Pathway gene Jagged-1 was found to be the cause of a disorder of bile duct development (Alagille syndrome) in 1997 by the lab lead by Nancy B. Spinner, PhD.
In addition to Jagged-1, mutations in another gene in the NOTCH signaling pathway, NOTCH2, has been shown to cause bile duct paucity and other features of Alagille syndrome, providing additional support for the role of NOTCH signaling. Since this time, the localization and timing of expression of NOTCH signaling genes have been extensively studied in mice and it has been shown that the Jagged-Notch pathway also regulates biliary development in zebrafish.
This work is being followed up to more fully define the abnormalities caused by Jagged-1 or NOTCH2 deficiency and the mechanism by which bile duct paucity occurs in humans.
Three disease models
Liver Center investigators have been working on human tissue to more clearly define the abnormalities of Jagged-1 and NOTCH2 in diseased livers. Work on NOTCH signaling is therefore taking place in human cells, the mouse and zebrafish, providing an outstanding opportunity to utilize the benefits of each of these systems.
An important area of research is the identification of additional genes involved in bile duct development. Liver Center investigators are actively working to define the genetic players in this process in the zebrafish and mouse respectively.
We anticipate that genes identified will be found to play a role in human diseases of the biliary system, and we will have an outstanding opportunity to study this, using human samples that we are banking at the hospital.