The Southern California Research Center for Alcoholic Liver and Pancreatic Diseases (ALPD) and Cirrhosis unifies 53 investigators from major academic institutions in Southern California and 4 foreign nations toward a common mission of promoting research, training, and outreach for ALPD and cirrhosis. Since its inception in 1999, the Center-supported components have doubled in number, resulting in a truly interdisciplinary program embracing basic science, education and training for undergraduate and graduate students, pre- and post-doctoral fellows, and community and global outreach programs. The Center's research base as measured by the total annual direct costs acquired by the Center members, has grown by 44% from $3.9 million five years ago to $5.6 million in 2007. The Center specializes in genetic loss and gain of function analysis facilitated by the mouse intragastric ethanol infusion (lEI) model and cell-type specific research aimed at delineation of the priming and sensitizing mechanisms. These investigational principles are complemented perfectly by innovative genetic and chimeric mouse models introduced by the laboratory of David Brenner who has joined the Center in spring of 2007. The Center-supported research has identified novel molecular targets for ALPD including: mitochondrial free cholesterol causing hepatic sensitization to TNFa; homocysteine inducing ER stress in hepatocytes; the regulatory 13 subunit of methionine adenosyltransferase promoting hepatocyte growth; iron signaling in hepatic macrophages priming IKK activation; stellate cell TLR4 priming liver fibrogenesis; PKC? for ethanol-induced sensitization for pancreatitis; and protective roles of caspases against necrotizing pancreatitis. The Center has also served as an important national resource by supporting 16 NIAAA or NIDDK-funded scientists across the nation via provision of the lEI models, shared samples from the models, and isolated different liver cell types, and by collaborating with three other NIAAA Alcohol Research Centers on basic research and outreach projects. The Center is committed to pursue its ultimate goal of defining the mechanisms of ALPD and cirrhosis and promoting the developments of new preventive and therapeutic modalities. This pursuit is facilitated by integration of liver and pancreas experts in Southern California and optimization of an interactive environment via concerted efforts of the cores with the unique expertise, cutting-edge basic research, effective pilot project and academic enrichment programs, and invaluable dissemination of scientific findings to regional and national communities.