# Molecular Mechanisms of Toxin-InducedBiliary Atresia

> **NIH NIH K08** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $82,728

## Abstract

PROJECT SUMMARY (NO CHANGES FROM ORIGINAL SUBMISSION)
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:** 10436003
- **Project number:** 3K08DK107910-05S1
- **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:** $82,728
- **Award type:** 3
- **Project period:** 2020-02-17 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436003

## Citation

> US National Institutes of Health, RePORTER application 10436003, Molecular Mechanisms of Toxin-InducedBiliary Atresia (3K08DK107910-05S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10436003. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*