# Enhancing mammalian liver repair and regeneration

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $364,500

## Abstract

PROJECT SUMMARY/ABSTRACT
There is incomplete understanding of liver cirrhosis pathogenesis and how it might be modulated. We recently
discovered that Arid1a, a component of the SWI/SNF ATP-dependent chromatin-remodeling complex, plays
potent roles in liver injury and regeneration. We found that liver-specific Arid1a knockout mice are highly
resistant to liver damage and fibrosis after multiple forms of chemical injury. These mice also have faster
regeneration after partial hepatectomy. Arid1a deficient livers show suppressed terminal differentiation and
increased proliferation after injuries, leading to more rapid and complete tissue repair, and in some cases
improved survival. Mice with whole-body Arid1a deficiency exhibit improved soft tissue and pancreatic β-cell
regeneration. These findings for the first time connect chromatin-remodeling machinery with tissue repair and
organ regeneration. This also suggests the existence of regeneration suppressor genes (analogous to tumor
suppressors), that when repressed or lost, promote tissue repair in the context of chronic liver disease. Given
that the loss of Arid1a from SWI/SNF chromatin-remodeling complexes improved hepatocyte fitness after
diverse injuries, our central hypothesis is that epigenetic changes have a major impact on tissue damage and
repair in cirrhosis progression and could be exploited for therapy. Several critical aspects of this hypothesis
demand further investigation. In AIM 1, we will biochemically characterize SWI/SNF complexes and how
they influence their genomic targets in the presence and absence of Arid1a. In AIM 2, we will determine
if mutations in chromatin-remodeling genes such as ARID1A appear in non-malignant human liver
disease tissues. We will then assess the functional impact of inactivating mutations in mouse models
of chronic liver disease progression. In AIM 3, we will determine if Arid1b, a closely related paralog that
has been observed to structurally substitute for Arid1a within complexes, is a functional antagonist of
Arid1a, and is thus responsible for enhancing regeneration in gain and loss-of-function mouse models.
Addressing these major questions with biochemical, cellular, and genetic approaches will increase our
understanding of how the SWI/SNF complex influences organ regeneration and liver disease pathogenesis.
Although it is not currently known if the suppression of ARID1A or activation of ARID1B will be practical in a
therapeutic sense, knowledge gained in this area may one day lead to novel strategies to counteract or reverse
the development of cirrhosis.

## Key facts

- **NIH application ID:** 9963264
- **Project number:** 5R01DK111588-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Hao Zhu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $364,500
- **Award type:** 5
- **Project period:** 2017-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963264

## Citation

> US National Institutes of Health, RePORTER application 9963264, Enhancing mammalian liver repair and regeneration (5R01DK111588-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9963264. Licensed CC0.

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