The University of Louisville (UofL) Hepatobiology and Toxicology (H&T) COBRE is a unique thematic center focused on liver research. The UofL H&T COBRE concentrates on the mechanisms and therapeutic strategies for multiple forms of liver disease/injury, including: Non-alcoholic fatty liver disease/non-alcoholic steatohepatitis—the most common liver disease in the US/worldwide, and is highly linked to the metabolic syndrome; Alcoholic Liver Disease—a common problem among those who drink; Environmental Toxicant Induced Liver Injury—an increasingly recognized problem, and Louisville has been a leader in this area; Hepatitis B and C—important causes of cirrhosis and hepatocellular carcinoma worldwide; Personalized Medicine—an increasingly important factor in medication efficacy, and most drugs are metabolized in the liver; and Drug-Induced Liver Injury—the most common reason drugs are removed from the market and an important cause of liver failure. This COBRE brings together experienced senior mentors/investigators and promising junior investigators to perform cross-cutting research on the unique topics of Hepatobiology and Toxicology. We address critical barriers in our understanding of the development/ progression of liver disease and we define targets for prevention/treatment that could transform clinical practice. Specific Aims of the Hepatobiology and Toxicology COBRE are to: 1. Expand and strengthen a thematically-focused program in Hepatobiology and Toxicology that helps build and sustain the overall research infrastructure at UofL. 2. Expand and strengthen the multidisciplinary program in research education, mentoring and career development in Hepatobiology and Toxicology, and systematically track and evaluate the progress. 3. Provide the necessary research resources and translational science/basic technologies to support state-of- the-art research in Hepatobiology and Toxicology and to ensure sustainability of the program. 4. Discover new mechanisms/molecular targets and effective means for preventing and/or treating liver diseases/toxicant exposures and communicate our findings to the public. In summary, Phase I strengthened UofL’s biomedical research infrastructure through the establishment of a thematic multidisciplinary center in hepatobiology and toxicology to enhance the ability of investigators to compete for independent funding. In Phase I, we met or exceeded our metrics, including 1) four of our investigators transitioning to independent research funding; 2) 91 mentee and 162 total publications; 3) new renovated laboratory space; 4) numerous presentations; 5) establishing new collaborations; and 6) >$75 million in total new grant funding by H&T members. This Phase II proposal builds on our Phase I success, extends and strengthens the scope of the program, and provides a roadmap for sustainability.