# Molecular Mechanisms of Toxin-InducedBiliary Atresia

> **NIH NIH K08** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $165,456

## Abstract

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.

## Key facts

- **NIH application ID:** 10135916
- **Project number:** 5K08DK107910-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Xiao Zhao
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $165,456
- **Award type:** 5
- **Project period:** 2020-02-17 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135916

## Citation

> US National Institutes of Health, RePORTER application 10135916, Molecular Mechanisms of Toxin-InducedBiliary Atresia (5K08DK107910-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10135916. Licensed CC0.

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