# Modeling genetic contributions to biliary atresia

> **NIH NIH R01** · EMORY UNIVERSITY · 2023 · $622,631

## Abstract

Project Summary/Abstract
Biliary atresia (BA) is an important and perplexing disease of neonates that has eluded major
discoveries of etiology and pathophysiology for decades. Recently, the NIDDK-supported
ChiLDReN network performed exome sequencing on a subset of BA individuals with cardiac and
abdominal laterality features–those with the BA Splenic Malformation (BASM) syndrome in order
to determine if there is a genetic etiology in this group with multi-organ developmental
dysmorphogenesis. Analysis of BASM exome sequences found several participants with
significant mutations in the ciliary gene PKD1L1, a gene associated with cardiac laterality defects,
but not yet linked to biliary tract disease. In order to explore mechanistic consequences to
impaired PKD1L1 signaling in humans, we developed an intrahepatic cholangiocyte-restricted
Pkd1l1Fl/Fl;Afp-Cre (LKO) mouse. Preliminary data indicates that absence of Pkd1l1 in the
developing mouse liver leads not only to early biliary dysmorphology, but an enhanced peribiliary
fibroinflammation at adult ages, moreso in the setting of distal obstruction after bile duct ligation
(BDL). These histologic features strongly mimic those seen in human BA livers. Aim 1 explores
the fibroinflammatory consequences of absent Pkd1l1 signaling in the LKO and other informative
Pkd1l1Fl/Fl cross-bred lines (including one with a human bile acid pool and another that will delete
Pkd1l1 in the entire biliary tree) and response to select bile acid based therapeutic interventions.
Aim 2 explores the delineation of early bile duct dysmorphology in developing prenatal and early
postnatal livers with lineage tracing and multiplexed spatial RNA studies. Finally, Aim 3 is an in
vitro set of experiments with cholangiocyte organoids, polarized Transwell cultures and 3d duct-
on-a-chip studies to define the molecular and signaling consequences in isolated Pkd1l1Fl/Fl and
LKO cholangiocytes. Taken together we anticipate that these 3 Aims will provide first-ever genetic
models of BA poised to discover new cellular and molecular mechanisms of biliary tract reactivity
and damage. In addition, testing of bile acid pathway-based agents in informative Pkd1l1 mouse
models may help provide supportive pre-clinical evidence to address the current paucity of
effective medical therapeutics in BA.

## Key facts

- **NIH application ID:** 10639240
- **Project number:** 1R01DK135815-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** SAUL J. KARPEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $622,631
- **Award type:** 1
- **Project period:** 2023-06-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10639240

## Citation

> US National Institutes of Health, RePORTER application 10639240, Modeling genetic contributions to biliary atresia (1R01DK135815-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10639240. Licensed CC0.

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