This proposal is a request for a Mentored Research Scientist Development Award (K01) from the National institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The candidate has demonstrated significant commitment to research activities in the area of the liver immune response as it pertains to liver diseases. The K01 Award would enable the candidate to build upon previous research experiences in immunology and gain the research skills in the drug-induced pathobiology and molecular biology of primary hepatocytes and sinusoidal endothelial cells to develop an independent research career in the function of liver innate immunity in drug-induced liver disease. The candidate proposes to begin research in this field by focusing on the hepatotoxicity of acetaminophen (APAP), since it is a common cause of acute liver failure and serves as a prototype. There is growing evidence that inflammatory mediators released by nonparenchymal inflammatory cells contribute to drug hepatotoxicity. The abundance of natural killer cells (NK) and NK cells with T cell receptors (NKT) in the liver raises the question as to what may be the role of these cells in APAP-induced liver injury. Therefore, the overall goal of this proposal is to understand the function of liver innate immune system with the specific focus to elucidate the role of NK and NKT cells in APAP-induced liver injury. The candidate propose that drug metabolism-dependent events may initiate hepatocyte and sinusoidal endothelial cell damage and sensitize them to inflammatory mediators released from liver innate immunity, i.e., NK cells, NKT cells, macrophages/Kupffer cells, and the ultimate severity of drug-induced liver injury in vivo may depend greatly on the downstream participation of liver innate immunity and their interplays. Preliminary studies suggest that NK and NKT cells play a critical role in the progression of APAP-induced liver injury because elimination of these cells significantly protected mice from APAP-induced liver injury, as evidenced by reduced serum transaminase levels, centrilobular hepatic necrosis and accumulation of inflammatory cells in the liver. It is anticipated that the data obtained from this proposal will define the function of liver innate immune system and the molecular mechanism of liver injury and contribute to our understanding of the pathogenesis of drug-induced hepatotoxicity as well as develop novel therapeutic strategies for drug-induced liver diseases. This K01 award will provide the candidate with the opportunity to be trained with broad knowledge and skills in the molecular biology and pathobiology of primary hepatocytes and sinusoidal endothelial cells under the guidance of Dr. Kaplowitz and the center members at the outstanding environment of USC Research Center for Liver Diseases.