# Elucidating chronic liver disease pathways using somatic genetics

> **NIH NIH DP1** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $754,400

## Abstract

PROJECT SUMMARY
Chronic liver disease is common and its pathogenic mechanisms are complex. There are no high throughput
genetic methods to uncover mechanisms that drive progression to cirrhosis. As a result, therapies that slow the
progression of liver disease are not currently available for most etiologies. The observation that our tissues
accumulate a large number of somatic mutations with age and chronic injury could provide a genetic window
into this process. Diseased livers harbor innumerable isolated islands of mosaic clones, but the identity and
functional importance of the somatic alterations within these clones remain undiscovered. In the past, somatic
mutations were generally assumed to be detrimental to health or drive cancer, but recently, some mutations
have been shown to exert adaptive effects that might benefit tissue health. In the liver, deep sequencing
experiments are beginning to reveal diverse somatic alterations, visually exemplified by the innumerable
nodules on cirrhotic livers. Stimulated by this landscape of mutations, we have developed in vivo genetic
screens to identify somatic mutations that have the greatest functional impact. Preliminary studies show that
some mutations can increase tissue regeneration and others can prevent metabolic liver disease. An emerging
concept is that cells can select for mutations that ameliorate, rather than cause, diseases such as
steatohepatitis or cancer. We believe that somatic mosaicism is an open frontier for human genetics, and
represents a potential source of unidentified disease genes and therapeutic targets. Using new technologies
developed in my lab, we propose to exploit somatic mosaicism as a genetic strategy to 1) identify adaptive
genetic pathways that are specific to particular liver disease etiologies, and 2) understand how mutant clones
expand within chronically damaged tissues, and potentially protect from disease in a therapeutic fashion.

## Key facts

- **NIH application ID:** 10937001
- **Project number:** 1DP1DK139976-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Hao Zhu
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $754,400
- **Award type:** 1
- **Project period:** 2024-09-15 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10937001

## Citation

> US National Institutes of Health, RePORTER application 10937001, Elucidating chronic liver disease pathways using somatic genetics (1DP1DK139976-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10937001. Licensed CC0.

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