Liver disease is a significant human health concern arising from diverse pathologies including drug overdose, alcoholism, infectious diseases, metabolic disorders, idiopathic causes, and cancer. The majority of the millions of Americans affected by these illnesses have poor therapeutic options. Pharmacologic interventions to enhance the restorative ability of the liver are desperately needed. They promise wide applicability for patients with chronic and acute liver disease. Patients with chronic liver disease often experience profound debilitation and inexorable progression of their disease. Treatments to enhance the ability of the liver to repair itself will ameliorate symptoms, prolong life, and obviate the need for liver transplantation. Patients with acute liver failure need short-term therapies to boost liver repair and allow recovery. Drugs to enhance liver repair have the potential to transform a patient death or need for liver transplantation into a complete cure. The goal of this proposal is develop drugs and methods to treat human liver disease. We seek to enhance the natural ability of the liver to repair itself. We will accomplish this by building on our preliminary studies that 1) identified a novel and modifiable signaling pathway critical for liver repair 2) demonstrated that drugs that affect this pathway enhance liver repair, cementing the clinical promise of our approach, and 3) developed novel methodology that allows unprecedented ability to manipulate genes in the liver and therefore ask fundamental research questions. This proposal will investigate three fundamental questions. First, we will identify specific molecules in the pathway that we discovered that are critical during liver repair. These studies are essential to understand the system and guide drug development. Next, we will determine the mechanism by which this pathway affects liver repair. These studies will reveal fundamental paradigms of liver repair and help predict how drugs which stimulate these mechanisms will affect patients. Finally, we will directly evaluate drugs that influence this pathway in a variety of liver injury models with direct relevance to human disease.