Clinical Resource for Alcoholic Hepatitis Inestigation

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Project Summary Alcoholic hepatitis (AH) is an acute manifestation of alcoholic liver disease (ALD), often with a grave prognosis. Despite the positive effects of corticosteroid treatment on short-term survival, this treatment is not ideal and approximately half of patients still die after a short time period. A major unmet need in the study of acute AH is the lack of a reliable animal model that mimics the entire spectrum of this disease in humans. Because translational research based on human samples has a key role in the understanding of mechanisms of alcoholic hepatitis, the collection of bio specimens from patients with severe AH could help substantially in the design of new therapeutic strategies. The liver transplant (LT) program for acute AH at Johns Hopkins provided a unique opportunity for us to create a clinical resource that now serves the alcohol research community and facilitates access to otherwise unavailable specimens. With support from this R24 grant, we have created a centralized facility for collecting human samples. The availability of a large amount of liver tissues and different liver cell types from severe AH patients to the alcohol research community has generated an innovative resource for translational research of acute AH. In the last funding period, we have provided our resource to 50 investigators from over 30 institutions/universities resulting in 18 publications in prestigious journals. The goal of this R24 grant renewal is to continue developing clinical resources for severe AH investigations and to continue meeting investigators’ current and increasing needs and liberally provide our resource to the entire alcohol research community. Specifically, we need to make more human tissues (explanted livers from patients with severe AH and other liver diseases) available to any investigators requesting these. In addition, we will provide expertise at Johns Hopkins to generate single-cell transcriptome and proteome databases from severe AH that may serve the alcohol research community and beyond. Specific aims will include maintaining a centralized facility for collecting human samples from patients with severe AH and other liver diseases and continually providing our clinical resources to any investigators requesting them, generating single-cell RNA- sequencing (scRNA-seq) datasets and proteomic and protein post-translational modifications (PTM) datasets from diseased livers in patients with severe AH or alcoholic cirrhosis (AC) and making them available to the alcohol research community for data mining/hypothesis generation. We will continue to promote collaboration through sharing our unique clinical resource.