ELUCIDATING MECHANISMS UNDERLYING DIFFERENTIAL CELLULAR SUSCEPTIBILITY TO TOXIC INJURY
We will utilize the biliatresone-induced injury model to understand cholangiocyte heterogeneity, with particular emphasis on uncovering genetic and epigenetic mechanisms underlying the differential susceptibility to toxic insults between epithelial cells lining the extrahepatic ducts (ie. gallbladder) versus intrahepatic ducts.
TO CHARACTERIZE THE ROLE OF CELLULAR STRESS RESPONSES IN MEDIATING CHOLANGIOCYTE INJURY
Biliatresone activates multiple evolutionarily conserved stress pathways including redox and proteomic stress responses, autophagy and the ubiquitin-proteasome system. We have already used biliatresone to functionally validate the importance of redox stress and heat shock response in modulating biliary injury. Ongoing investigation employs integrated genetic and pharmacological approaches to interrogate the functional relevance of other potentially involved stress signaling pathways and dissect the complex interplay between these processes.
ESTABLISHING ADDITIONAL MODELS OF BILIARY ATRESIA
We are currently using biliatresone to establish novel models of biliary injury and biliary atresia in mouse and iPSC-derived cholangiocytes. Establishment of these models will allow us to expand upon our previous findings and to further our understanding of key questions not addressable using the zebrafish.