# Building a functional biliary system from hepatocytes

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $434,900

## Abstract

Project Summary/Abstract
This application targets the unmet medical needs of patients with bile duct paucity who often develop severe
cholestatic liver injury that currently is only curable by liver transplantation. Our application builds on our finding
that hepatocytes can form intrahepatic bile ducts (IHBDs) that function to reverse cholestasis in a mouse
model of severe IHBD paucity. Conversion of hepatocytes-to-cholangiocytes has been reported, but our mouse
model establishes that hepatocytes can build a therapeutically effective biliary system from scratch. We
hypothesize that our mouse model has revealed the full potential of hepatocyte-to-cholangiocyte conversion
because of the severity of its IHBD paucity and its unique genetic makeup, affecting both NOTCH and
TGFbeta signaling, the main regulators of bile duct development. We propose to identify the mechanisms
responsible for spontaneous IHBD restoration from hepatocytes in our mouse model with the long-term goal of
enlightening tissue engineering approaches and to develop a therapy for diseases associated with bile duct
paucity. In Aim 1 we will define the interplay between NOTCH and TGFbeta driving conversion of hepatocytes-
to-cholangiocytes and assembly into IHBDs. For this we will use in vivo mouse models to perform
pharmacologic and genetic approaches modulating TGFbeta signaling for examining the “steps” (conversion
and morphogenesis) of hepatocyte-derived de novo IHBD formation. In addition, we will investigate the
mechanism by which loss of a TGFbeta effector influences the association of transcriptional cis-regulatory
complexes to induce hepatocyte-to-cholangiocyte transdifferentiation. Aim 2, in which we will define the
transcriptional network driving conversion of hepatocytes-to-cholangiocytes and assembly into IHBDs will also
inform these efforts. For this we will investigate in converting hepatocytes in vivo which transcription factors are
active and validate their efficacy in primary hepatocytes stabilized in a micropatterned co-culture system and a
cholangiosphere morphogenesis assay. Using the insight gained from these experiments, we will express
effectors of biliary differentiation and tube formation in vivo using non-integrating, nontoxic adeno-associated
viral vectors for gene delivery to hepatocytes. Our research will generate new insight into the molecular
regulation of hepatic cell identity, biliary development and regeneration.

## Key facts

- **NIH application ID:** 9985802
- **Project number:** 5R01DK107553-05
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Stacey S Huppert
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $434,900
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985802

## Citation

> US National Institutes of Health, RePORTER application 9985802, Building a functional biliary system from hepatocytes (5R01DK107553-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9985802. Licensed CC0.

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