# Injury, progression, and fibrosis of the extrahepatic bile duct

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $365,625

## Abstract

PROJECT SUMMARY
Biliary atresia (BA) is a fibro-obliterative disease of the bile ducts, especially the extrahepatic ducts (EHBDs),
that afflicts neonates around the world. BA is the most common indication for liver transplant in the pediatric
population, with 50% of patients requiring transplant by age 2 and most of the rest before adulthood. The
etiology and early course of the disease are unknown; however, important recent data suggest that BA results
from a prenatal environmental insult (sparing the mother) that is followed by progression of the original injury
after birth.
This proposal seeks to answer three key questions in BA: 1) Why is toxicity specific to neonates? 2) What
determines repair versus progression of cholangiocyte injury? and 3) How and why does fibrosis occur in the
EHBD? Our underlying hypothesis is that the answers to these questions are found in the unique features of
the neonatal biliary system: that BA results from an injury that occurs in the context of a developmentally
immature bile duct with anatomic features that make it susceptible to injury and promote progression of
damage and a fibrotic response.Our preliminary work identified key features of the neonatal bile ducts that
potentially increase their susceptibility to injury. These include lack of a protective apical glycocalyx on
cholangiocytes and immature cholangiocyte cell-cell junctions. We also showed that the submucosa of the
neonatal EHBD contains a large population of fibrogenic cells that are “primed' to respond to insults and that
the anatomical structure of the neonatal submucosa may propagate injury.We developed two unique tools to
study the role of duct immaturity in susceptibility and response to injury. First, we developed a mouse model of
prenatal EHBD damage. We identified and synthesized a previously unknown isoflavonoid biliary toxin,
biliatresone, that causes EHBD injury in fetal and neonatal mice after treatment of pregnant mothers. Damage
is worsened by humanizing the bile acid profile. This model will enable us to use genetically-modified and
specially-treated mice to investigate the importance of neonatal duct susceptibility factors in injury. Second, we
developed a microfluidic bile duct-on-a-chip device that allows us to culture neonatal, adult, and genetically-
modified cholangiocytes in a confluent, impermeable monolayer, to apply various treatments selectively to the
apical or basal surface, and to determine their impact on key cholangiocyte functions, including the
permeability barrier.Our three specific aims use these and other tools we have developed to study: 1) neonatal
susceptibility to injury, including the role of the glycocalyx; 2) the determinants of injury progression, including
the role of bile acids; and 3) the identity of the fibrogenic cells of the EHBD and the role of submucosal
architecture in the spread of injury. This work has the potential to both significantly shift our understanding of
BA and lead to new therapeut...

## Key facts

- **NIH application ID:** 10200799
- **Project number:** 5R01DK119290-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** REBECCA G WELLS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $365,625
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200799

## Citation

> US National Institutes of Health, RePORTER application 10200799, Injury, progression, and fibrosis of the extrahepatic bile duct (5R01DK119290-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10200799. Licensed CC0.

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