# Generation and characterization of a humanized mouse model of alcoholic liver disease

> **NIH NIH R21** · YALE UNIVERSITY · 2021 · $240,781

## Abstract

Generation and characterization of a humanized mouse model of Alcoholic liver disease
Project Summary/Abstract
Alcoholic Liver Disease (ALD) is the first cause of liver related deaths in USA. However, effective treatment
options for ALD are very limited due to the lack of suitable in vivo models that recapitulate the full spectrum of
ALD. In human ALD, there is marked inflammation, liver damage and steatosis. On the other hand, mouse
models of ALD display very mild phenotype. Thus, there is an urgent but still unmet need to develop a clinical
relevant ALD model that can capture the key features of human disease. We have already developed a
humanized murine system in which mice have been humanized at key loci by knock-in of human genes
(MISTRG-6-Fah-KO mouse) and have been further humanized at a cellular level by engraftment of human
hepatocytes and CD34+ stem cells. These mice support human liver hepatocytes, immune, endothelial and
stellate cell populations. Crucially, we have shown that the treatment of humanized MISTRG-6-Fah-KO mice
with Lieber-DeCarli ethanol liquid plus a single binge ethanol induced higher liver inflammation and liver damage
than in non-humanized. Therefore, we hypothesize that the exposure of human cells to alcohol in vivo can better
mimic the ALD pathology of humans. To test this hypothesis, we are proposing to treat the humanized MISTRG-
6-Fah-KO mice with alcohol diet and to examine disease pathology in comparison to humans. Next, we will
examine the transcriptional state and the composition of human liver cells of MISTRG-6-Fah-KO mice upon
alcohol treatment and how much is the extent of their overlap with the human ALD. With the proposed
experiments, we aim to develop and characterize the first human-clinical relevant alcoholic liver damage model
in the humanized MISTRG-6-Fah-KO mice. In that model, human immune cells and human effector cytokines
will drive the development of inflammation and liver damage and human hepatocytes will drive the development
of steatosis.

## Key facts

- **NIH application ID:** 10196181
- **Project number:** 1R21AA029206-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Richard A Flavell
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $240,781
- **Award type:** 1
- **Project period:** 2021-05-10 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10196181

## Citation

> US National Institutes of Health, RePORTER application 10196181, Generation and characterization of a humanized mouse model of alcoholic liver disease (1R21AA029206-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10196181. Licensed CC0.

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