AH (AH) is a major cause of morbidity and mortality due to a lack of effective treatments for this condition. As stated in RFA-AA-12-007, translational investigations are needed on new mechanisms and suitable pharmacological agents relevant to AH. This application is one of three that comprise a consortium (Translational Research and Evolving Alcoholic Hepatitis Treatment; TREAT) and include Indiana University, Virginia Commonwealth University, and Mayo Clinic. The Overall goals of the TREAT consortium are to perform patient oriented translational studies that will uncover and test new pharmacologically relevant targets for the treatment of AH. This specific TREAT-Mayo application will focus on expansion of recent studies that have revealed a key role for caspase dependent cell death pathways as a pathogenic culprit in AH. In this proposal, we will test the Central Hypothesis that the novel caspase inhibitor emricasan is safe and effective in patients with AH through a mechanism involving inhibition of hepatocellular apoptosis and sterile necrosis. We will also support the broader goals of the TREAT consortium by recruiting patients for a well annotated registry and by providing a mechanistic resource for human serum and liver tissue analyses that are broadly pertinent to liver injury, inflammation, and cell death. Thus, the Specific Aims of thi application are to: 1) Develop longitudinal observational cohort of patients with AH. We will develop a prospective multicenter registry of patients with well characterized AH and suitable controls that serves as the clinical and biosample based foundation for conducting human therapeutic (as described in Aim 2) and novel mechanistic (as described in Aim 3) studies. 2) Test the hypothesis that 4-week emricasan administration will improve survival in patients with AH. We will conduct an early phase randomized, blinded, placebo controlled study, which will include a special population of patients with severe AH who are not otherwise candidates for corticosteroid therapy based on specific contraindications. 3) Test the hypothesis that apoptosis and sterile necrosis contribute to development of AH and are pathogenic targets of emricasan. We will measure serum and liver tissue markers of both apoptosis and sterile necrosis to inform our understanding of how these molecular processes contribute to liver injury and inflammation in human AH. Thus, this study, submitted by a group of investigators with extensive experience in clinical AH and basic liver injury, will determine the safety and potential efficacy of a novel and innovative therapy, the caspase inhibitor emricasan, in patients with AH. Additionally, the proposed mechanistic analyses will elucidate how distinct cell death pathways contribute to human AH and how caspase inhibition abrogates these pathways thereby inhibiting liver injury and inflammation in patients with AH. Our track record in patient recruitment trials and expansive resources in liver injury pathways will also provide key components for the broader success of this consortium. In total, this application will provide a major step in advancing our understanding of the devastating condition of AH. PUBLIC HEALTH RELEVANCE: Alcoholic hepatitis is a major cause of morbidity and mortality in humans. New approaches to interfere with the development of this condition and its complications would be of great value.