# Genetic regulation of ductular reaction in liver injury and regeneration

> **NIH NIH R01** · EMORY UNIVERSITY · 2023 · $399,722

## Abstract

PROJECT SUMMARY
 The liver exhibits remarkable capacity for regeneration, but chronic injury or severe acute damage can
overwhelm compensatory responses and result in liver failure. The need for transplantable livers regularly
exceeds the donor pool, necessitating the development of new regenerative medicine-based therapies and a
deeper understanding of the liver’s endogenous repair mechanisms. This proposal seeks a mechanistic
understanding of gene regulatory networks underlying ductular reaction (DR), a damage response associated
with a broad range of liver injury and disease. DR is defined by the proliferative expansion of biliary epithelial
cells (BECs) and can involve context-dependent lineage conversion between mature hepatocytes and BECs that
contributes to tissue regeneration. The genetic regulation of DR remains poorly understood, including how BECs
balance proliferation and phenotypic plasticity. Sox9 is a transcription factor required for stem/progenitor cell
function in a number of epithelial tissues and has been shown to establish cellular identity through genome-wide
effects on the chromatin landscape. In the liver, Sox9 is required for timing of BEC specification in development
and is broadly expressed in adult BECs. Our lab recently used a Sox9EGFP transgene to study BEC heterogeneity
and showed that Sox9 is expressed at distinct levels in subpopulations of BECs and peribiliary hybrid
hepatocytes (HybHeps) during homeostasis and cholestasis. New findings from our lab also demonstrate
abnormalities in BECs of adult Sox9 knockout mice. The central hypothesis of this proposal is that Sox9 functions
as a master regulator of DR, by inhibiting proliferation and promoting BEC identity. The following specific aims
will test this hypothesis: Aim 1A will determine the role of Sox9 in damage induced BEC proliferation, through
the use of the Sox9EGFP allele and (1) combined BEC/hepatocyte or (2) BEC-specific Sox9 knockout mouse
models. Aim 1B will determine the role of Sox9 in bi-directional BEC-to-hepatocyte plasticity, through
complementary in vivo lineage tracing and in vitro organoid assays. Aim 2A will map the chromatin regulatory
landscape of DR, by integrating transcriptomics and chromatin assays in BEC subpopulations during liver injury.
Aim 2B will determine the genomic regulatory impact of Sox9 in DR by applying single cell multi-omics to BEC-
specific Sox9 knockout mouse models. The data generated in this project will provide fundamental mechanistic
insight into genetic regulation of DR and identify regulatory nodes for therapeutic targeting to enhance
regeneration in end stage liver disease.

## Key facts

- **NIH application ID:** 10595652
- **Project number:** 5R01DK132653-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Adam David Gracz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $399,722
- **Award type:** 5
- **Project period:** 2022-04-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10595652

## Citation

> US National Institutes of Health, RePORTER application 10595652, Genetic regulation of ductular reaction in liver injury and regeneration (5R01DK132653-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10595652. Licensed CC0.

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