# Roles for Pkd1l1 in bile duct development

> **NIH NIH F31** · EMORY UNIVERSITY · 2023 · $38,633

## Abstract

PROJECT SUMMARY
Biliary atresia (BA) is the main indication to transplant any solid organ in infants less than 1 year of age and has
eluded major discoveries of etiology and pathophysiology for decades. BA is a neonatal liver disease that is best
characterized by fibroinflammatory obstruction of both intra- and extrahepatic bile ducts. Through exome
sequencing of a subset of BA individuals with heterotaxic (laterality) features (those with the BA Splenic
Malformation syndrome), several participants were identified with biallelic damaging mutations in the ciliary gene
PKD1L1 (Polycystic kidney disease 1 like 1). To explore mechanistic consequences of impaired PKD1L1
signaling in humans, we developed an intrahepatic cholangiocyte-restricted Pkd1l1Fl/Fl;Afp-Cre (LKO) mouse.
Recently published data indicates that the absence of Pkd1l1 in the developing mouse liver leads to early biliary
dysmorphology and 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,
offering a novel opportunity to discover specific cellular and molecular insights into BA’s rapid and profound
pathogenesis. There are two paradigms that must be uncovered to provide a more thorough understanding of
Pkd1l1, and thus the molecular pathogenesis of BA. First, the consequences of absent Pkd1l1 in the developing
biliary tree that leads to adulthood biliary fibroinflammation are unknown. Second, the mechanism of Pkd1l1
signaling within cholangiocytes, which when absent contributes to biliary pathology, remains to be elucidated.
The overarching hypothesis in this proposal is that Pkd1l1 is required for proper biliary development
and signaling. This hypothesis will be tested through the following two aims. Aim 1 explores the delineation
and characterization of early bile duct dysmorphology in developing prenatal and early postnatal livers. This aim
will utilize the recently developed Pkd1l1Null/Fl (NullFl) and Pkd1l1Null/Fl;Afp-cre (NullLKO) mouse lines. Aim 2 is
an in vitro set of experiments with isolated cholangiocyte studies to define Pkd1l1-interactors and signaling
consequences, specifically in response to various bile acids, in isolated Pkd1l1Fl/Fl and LKO cholangiocytes.
Taken together, we anticipate that these two aims will discover new cellular and molecular mechanisms of biliary
tract development and signaling. In addition, information stemming from these Pkd1l1-based mouse models will
help provide supportive pre-clinical evidence to address the current paucity of effective medical therapeutics in
BA.

## Key facts

- **NIH application ID:** 10751883
- **Project number:** 1F31DK137565-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Dominick Hellen
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $38,633
- **Award type:** 1
- **Project period:** 2023-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10751883

## Citation

> US National Institutes of Health, RePORTER application 10751883, Roles for Pkd1l1 in bile duct development (1F31DK137565-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10751883. Licensed CC0.

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