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American Liver Foundation
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New York, New York 10006
American Liver Foundation Postdoctoral Research Fellowship Award
Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
“The role of peribiliary glands in development and repair of extrahepatic bile ducts”
Recent advances point to an important role of the immune system as biological effectors of epithelial injury and obstruction of bile ducts in the pathogenesis of biliary atresia. Here, Dr. DiPaola proposes to study the biliary epithelium as the biological target in disease pathogenesis. In preliminary experiments, his lab found that peribiliary glands of extrahepatic bile ducts from neonatal and adult mice elongate and form networks of epithelial cells along the length of the epithelium proper. In this application, he plans to test the hypothesis that peribiliary glands are populated by undifferentiated cells and are critical to epithelial integrity in pathological states. This will be tested in three inter-related aims. In the first aim, he will determine the anatomical structure and the progenitor phenotype of peribiliary glands. This will be done by performing whole mount in situ staining using antibodies to cytokeratin and the endoderm transcription factors Pdx1 and Sox17. In the second aim, he will define the regulatory role of Pdx1 and Sox17 in the development of peribiliary glands. In these experiments, he will use mice that have the conditional inactivation of the Pdx1 and Sox17 genes and determine if their loss impairs morphogenesis of peribiliary glands. In the third aim, he will explore the role of peribiliary glands in the reparative response to injury of extrahepatic bile ducts. Dr. DiPaola’s experimental approach will include two injury models: 1) epithelial injury induced by rotavirus infection in neonates as a model of biliary atresia, and 2) bile duct ligation in adult mice. Each model will contain mice with conditional inactivation of Pdx1 and wild type controls. Extrahepatic bile ducts will be microdissected and analyzed for epithelial integrity by standard hematoxylin/eosin staining, involvement of peribiliary glands by whole mount in situ staining, and cell proliferation by staining for Ki67. These experiments will provide insight into the composition of peribiliary glands by cells with immature (progenitor) cell phenotype, the influence of endoderm factors in gland morphogenesis, and their role in the reparative response of the bile duct epithelium to an injury. The line of experiments proposed herein will guide future mechanistic studies on how peribiliary glands and their cellular networks contribute to pathogenesis of biliary atresia.
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