Molecular Subtypes for Targeted Therapies in Alcoholic Hepatitis

DESCRIPTION (provided by applicant): The development of new targeted therapies for alcoholic hepatitis (AH) is one of the more urgent needs in clinical hepatology. To reach this goal, large multidisciplinary networks are required. The proposed initiative Integrated Approaches for Identifying Molecular Targets in Alcoholic Hepatitis (InTeam) will coordinate a multidisciplinary group composed of clinicians, physician-scientists, basic scientists and bioinformatics experts. The overarching hypothesis of InTeam is that the most rational way to provide a useful framework for future clinical trials in (AH) consists of the (i) determination of ey drivers of the disease process, (ii) classification of molecular profiles and subtypes of AH, and (iii) identification of druggable targets based on both key drivers and molecular classification. Moreover, mouse models for AH are lacking making it impossible to evaluate promising targets in preclinical mouse studies in a meaningful manner. For this purpose, InTeam will integrate data obtained from molecular pathology studies in human AH and functional studies of key pathways in animal models. The proposed InTeam consortium includes three research projects, ten clinical centers, a Human Biorepository and a Mouse Models Core. The Human Biorepository Core will generate the to-date largest collection of samples from patients with AH from 10 academic liver centers and a comprehensive database that will serve as a basis for the proposed translational studies and be a valuable asset for the broader scientific community. The Mouse Models core will conduct murine studies after establishing and evaluating mouse models of AH based on the pathophysiology and molecular drivers of human AH determined by this consortium. The three scientific projects will combine a thorough molecular characterization of patients with AH with studies on key and targetable pathways that drive key aspects of AH disease progression and outcome such as inflammation, injury and regeneration. Project 1 (Molecular Subtypes for Targeted Therapies in Alcoholic Hepatitis, PIs: Ramon Bataller and Philippe Mathurin) will identify molecular and cellular drivers of AH to provide a molecular classification using RNA sequencing, kinomic, metabolomic and novel systems biology approaches, and determine contributors to unfavorable outcome and the associated progenitor cell accumulation. Project 2 (DAMPs for Targeting Alcoholic Hepatitis, PIs: Robert Schwabe and Wajahat Mehal) will explore the contribution of damage-associated molecular patterns (DAMPs) including HMGB1 and mitochondrial DAMPs, to the development of hepatic and systemic inflammation, and organ damage in AH. Project 3 (Microbiota as Therapeutic Targets in Alcoholic Hepatitis, PIs: Bernd Schnabl and David Brenner) will using cutting-edge pyrosequencing and bioanalytical tools to investigate changes in the intestinal microbiome, metatranscriptome and metabolome as potential contributors and targets for therapeutic interventions in AH. In summary, the InTeam network will provide a unique combination of the to-date largest systematic sample and data collection of AH patient samples with a strong group of scientists dedicated to translational AH research and a large network of participating clinical centers. We anticipate that the systematic approach and translational nature of this consortium will advance the understanding of AH, and provide novel approaches for its prevention and treatment.