# Injury, Progression, and Fibrosis of the Extrahepatic Bile Duct

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $343,200

## Abstract

PROJECT SUMMARY
The goal of this proposal is to determine the role of fetal vs. adult wound healing programs – and the switch from
one to the other that occurs around birth – in the response to fetal/early neonatal extrahepatic bile duct injury,
such as occurs in biliary atresia (BA). BA is a rare disease occurring worldwide that it is thought to occur from a
prenatal environmental insult – affecting only the fetus – to the extrahepatic bile duct (EHBD). Babies appear
healthy at birth, but undergo rapid progression of the disease to fibrosis and obstruction of the duct and cirrhosis
of the liver. There are three major unanswered questions that motivate this proposal:
  Why does an EHBD insult during pregnancy affect only the fetus?
  Do some babies with fetal EHBD injury recover, and if yes, why recovery rather than fibrosis?
  Why does the disease progress so rapidly after birth?
Our preliminary data suggest that prenatal EHBD injury leads to a program of fetal wound healing in the initial
response of the fetal EHBD to injury. Fetal wound healing, which has been reported in multiple tissues, results
in regeneration rather than scarring and is particularly notable for the deposition of high molecular weight
hyaluronic acid (HA) rather than type I collagen, with a growth factor milieu that includes IL-10 rather than TGF-.
The switch from a fetal to an adult wound healing program occurs late in gestation.
We hypothesize that fetal and adult wound healing programs, in sequence, determine the response to fetal
EHBD injury; that both have the potential to enhance damage and injury progression; and that co-opting these
responses would have a major therapeutic benefit. We propose to test these hypotheses through 2 specific
aims that study wound healing in sequence from the fetus to the newborn, including the impact of natal stress
on the transitional program between fetal and adult: 1) Define the nature of fetal wound healing and its impact
on the injury response in the fetal EHBD; and 2) Determine the impact of birth-associated stress and the switch
to an adult wound healing program in the context of an HA-laden EHBD after the events of fetal wound healing.
The proposed work introduces a new concept – fetal wound healing – to the study of BA. Understanding fetal
wound healing in BA, both its positive and negative effects, will be essential in the development of potentially
transformative treatments.

## Key facts

- **NIH application ID:** 10861874
- **Project number:** 5R01DK119290-06
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** REBECCA G WELLS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $343,200
- **Award type:** 5
- **Project period:** 2019-08-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10861874

## Citation

> US National Institutes of Health, RePORTER application 10861874, Injury, Progression, and Fibrosis of the Extrahepatic Bile Duct (5R01DK119290-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10861874. Licensed CC0.

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