# Establishing Sox9 as a regulator of intrahepatic bile duct development and regeneration

> **NIH NIH F31** · EMORY UNIVERSITY · 2022 · $46,752

## Abstract

PROJECT SUMMARY
The liver exhibits remarkable capacity for regeneration, but chronic injury or severe acute damage can
overwhelm regenerative mechanisms and lead to end-stage liver disease. The lack of effective medical therapies
combined with insufficient donor organ availability necessitates the development of new regenerative medicine-
based therapies and a deeper understanding of the basic mechanisms of liver repair. The transcription factor
Sox9 is required for stem/progenitor cell function in a number of epithelial tissues and has been shown to
establish cellular identity. In the liver, Sox9 is required for timing of biliary epithelial cell (BEC) specification in
development and is broadly expressed in adult BECs. Sox9 deficiency worsens cholangiopathy in mouse models
of Alagille Syndrome. My preliminary data demonstrate ductal paucity in Sox9 knockout mice, suggesting a
central role for Sox9 in BEC specification. This proposal seeks to define functional regulation of intrahepatic BEC
networks by Sox9, during development and injury-associated ductular reaction (DR). DR is a common
characteristic of liver disease and is defined by the proliferative expansion of BECs. Furthermore, based on
damage type, timing, and/or extent of damage, DR can involve lineage conversion between mature hepatocytes
and BECs that contributes to tissue regeneration. The genetic regulation of DR remains poorly understood. The
central hypothesis of this proposal is that Sox9 is required to establish proper intrahepatic BEC
networks in development and ductular reaction. I will test this hypothesis with the following specific aims:
Aim 1A will establish the developmental requirement of Sox9 to form functional intrahepatic bile ducts in mice
through the use of histology, bile acid assays, organoid assays, and 3D tissue imaging. Aim 1B will investigate
the role of Sox9 in specifying BEC subpopulations through scRNA-seq. Aim 2 will determine how Sox9 maintains
adult BEC populations during DR using inducible Sox9 knockout mice. BEC function will be assayed by liver
serum biochemistry, histology, and lineage tracing. This project will determine how Sox9 establishes and
maintains BEC populations and provide me with training towards my goal of obtaining a research-focused faculty
position studying GI tissue homeostasis and regeneration. This work is significant because the findings will help
develop an understanding of basic mechanisms of liver repair that can be used to identify novel targets for
therapeutics to restore liver function in end stage liver disease.

## Key facts

- **NIH application ID:** 10537874
- **Project number:** 1F31DK134199-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Hannah Rose Hrncir
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10537874

## Citation

> US National Institutes of Health, RePORTER application 10537874, Establishing Sox9 as a regulator of intrahepatic bile duct development and regeneration (1F31DK134199-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10537874. Licensed CC0.

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