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

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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.