ANIMAL CORE - ABSTRACT The Animal Core is the center’s most active scientific hub for catalyzing in vivo genetic, molecular and cellular research on the pathogenesis of alcohol-associated liver and pancreatic diseases (ALPD) pursued by investigators within and outside of the center. The Core now generates 16 different versions of preclinical models including a mouse model of alcohol-associated hepatitis which utilizes a hybrid feeding technique of ad lib consumption of solid Western diet and intragastric feeding of ethanol diet plus weekly ethanol binge. The Core also developed Western alcohol diet (WAD)-based tumor-promotion models for hepatocellular carcinoma (HCC) and patient-derived HCC xenograft (PDX) model; alcohol diet-based promotion of pancreatic adenocarcinoma in KrasG12/D mice; and liver tumorigenesis by orthotopic transplantation of liver tumor-initiated stem cell-like cells (TICs) in immunocompetent C57/Bl6 mice fed alcohol diet. Most recently, the Core has developed a novel humanized HCC mouse model with humanization of parenchymal and non-parenchymal liver cells and immune cells using fetal liver cells. In this model, a combination of CRISPR/Cas9-based mutations of ARID1A and CTNNB1 common in alcohol-associated patient HCC in hepatoblasts and WAD feeding results in a heightened HCC incidence in FRG (Fah-/-;Rag2-/-;Il2rg-/-) mice, serving as an invaluable tool for studies on gene-environment interactions and pre-clinical therapeutic testing in a humanized setting. These models developed and produced by the Core will promote translational research on advanced ALPD and cirrhosis. During the current cycle, the Core produced 2,401 model mice to serve 24 center and 16 non-center investigators, supporting 30 publications, 21 grant acquisitions and 8 applications by the center members and 6 grants and 7 applications by non-center investigators. In addition, the Core’s Repository Program has provided 333 samples to 16 investigators from 13 institutions across the nation to support their research mostly funded by NIAAA. In the next cycle, the Animal Core will continue pursuing the following six specific aims to fulfill its mission of serving the nation to advance ALPD research: 1) to serve as a national resource by provision of 16+ different versions of rodent models which optimally recapitulate advanced and clinically relevant pathologic spectra of ALPD; 2) to provide the humanized HCC mouse model as a widely available service; 3) to support in vivo genetic analysis and cell fate mapping analysis; 4) to promote cell type specific research via close collaboration with the center’s Integrative Liver Cell Core for better elucidation of cell fate regulation underlying ALPD spectra; 5) to render full support to early-stage scientists including those funded by the Pilot Project Core to maximize their potential for a successful transition to independent investigators; and 6) to stimulate collaboration and synergize productivity by shared use of...