Molecular Mechanisms of Toxin-InducedBiliary Atresia

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PROJECT SUMMARY Biliary atresia (BA) is a neonatal cholangiopathy that is the leading indication for liver transplantation in the pediatric population. The etiology of human BA remains obscure, however, BA epidemics in newborn Australian livestock associated with maternal ingestion of the Dysphania species plant support a toxic etiology. Using an in vivo zebrafish biliary secretion assay, we have isolated biliatresone, a novel plant isoflavonoid with selective extrahepatic biliary toxicity that is likely responsible for the Dysphania BA syndrome (1). This toxin- mediated BA model recapitulates the cardinal features of human BA and thus can be used to model this rare but important pediatric liver disease. Biliatresone is a strong electrophile and we have shown that redox stress and proteomic stress play critical roles in biliatresone toxicity. Specifically, we have found that: 1) extrahepatic cholangiocytes exhibit a significantly more oxidized glutathione (GSH) redox potential both at baseline and after treatment with biliatresone compared to intrahepatic cholangiocytes and hepatocytes; and 2) biliatresone toxicity can be altered through pharmacologic and genetic manipulation of GSH redox homeostasis (2). The overarching goals of this proposal are to continue use biliatresone as an injury model for defining cholangiocyte stress responses to toxic insults and to explore the links between stress responses and genetic susceptibility to biliary injury. The proposal consists of two specific aims. In Aim 1, we will define mechanisms of liver redox heterogeneity that confer differential susceptibility to toxic injury in the zebrafish model. In Aim 2, we will define links between cholangiocyte proteomic and redox stress responses and genetic susceptibility to redox- induced cholangiocyte injury using zebrafish and human cholangiocytes derived from induced pluripotent stem cells. The proposed experiments will reveal novel information about the molecular mechanisms underlying the pathogenesis of BA that we hope will spur the development of new therapeutic strategies for BA and other cholangiopathies.