# Systems genetics dissection of non-alcoholic steatohepatitis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $645,684

## Abstract

PROJECT SUMMARY
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder which comprises of a
spectrum of hepatic abnormalities ranging from simple steatosis to steatohepatitis (NASH), which can progress
to cirrhosis and hepatocellular carcinoma. Despite significant research efforts, the etiology of this disease is
poorly understood; in particular, factors associated with progression from steatosis to NASH are unknown. We
have developed mouse models from the Hybrid Mouse Diversity Panel (HMDP) that exhibit the spectrum of
NAFLD observed in humans. The overall goal of our proposal is to use population-based approaches in mice
to identify pathways and higher order biological networks that contribute to the development and progression of
NAFLD. Using Mergeomics, an association-based modeling method we developed, we previously identified
and validated several genes associated with steatosis from a cohort of HMDP mice fed a high fat, high sucrose
diet. Applying the same strategy to a novel transgenic HMDP mice model of NASH, we have now identified
several high confidence NASH candidate genes. In Aim 1, we will perform transcriptomic and metabolomics
profiling on resistant and susceptible strains to examine the progression of NASH. We will identify and validate
candidate genes for NASH progression using multi-omics approaches and Adeno-Associated Virus (AAV)
vectors for rapid screening in mice. We will also identify cell-specific changes in gene expression and cell
composition related to liver fibrosis and other NAFLD features. This will allow us to follow functional changes in
the major hepatic cell types as well as populations of stellate cells and infiltrated inflammatory cells during
NASH progression. In Aim 2, we will examine five prioritized genes contributing to hepatic fibrosis, including
one gene, Mgp, that we recently validated using knockout mice. Mechanistic studies will be performed to
investigate how these genes affect fibrosis. Additional candidate genes identified in Aim 1 will be examined
with a similar strategy. Results from these studies will reveal the underlying genetic mechanisms contributing
to NAFLD and may identify potential therapeutic targets.

## Key facts

- **NIH application ID:** 10434833
- **Project number:** 5R01DK117850-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Aldons Jake Lusis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $645,684
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434833

## Citation

> US National Institutes of Health, RePORTER application 10434833, Systems genetics dissection of non-alcoholic steatohepatitis (5R01DK117850-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10434833. Licensed CC0.

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