Alcoholic hepatitis (AH) is an acute manifestation of alcoholic liver disease (ALD) often with a grave prognosis. Despite the positive effects of corticosteroids 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 alcoholic hepatitis 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. Since most AH deaths occur within 2 months of onset, early liver transplantation is attractive but controversial because of the historic requirement of 6-month abstinence from alcohol. In 2012 following the French report we began a program for transplantation of patients with acute AH at Johns Hopkins and have performed 20 such transplants with 95% 1 year survival, results similar or superior to those reported in the NEJM. As few other centers and none in our region are undertaking these cases we are a regional referral center for AH patients. Likewise, when these patients undergo liver transplantation, a native hepatectomy is performed and their explanted liver serves as an unusual resource for the study of AH. To promote innovation and translational research in the field, we are seeking support to develop a clinical resource of severe alcoholic hepatitis that serve the alcohol research community. With this R24 support, we will collect livers and data from patients with severe AH during transplantation, and wedge biopsies from donor livers as controls. Specifically, we will isolate hepatocytes, hepatic stellate cells, Kupffer cells, sinusoid endothelial cells and infiltrating lymphocytes from the explanted liver. Support from bio preservation experts at the Johns Hopkins hospital will provide assistance in appropriate sample processing and storage to ensure quality experimental results. We will establish a centralized database of de-identified samples for the purpose of promoting access to otherwise unavailable specimens, collaboration, efficiency, and progress towards a cure. In collaboration with experts from the High Throughput Biology Center at Johns Hopkins, we will also utilize this resource to perform transcriptome and proteome analysis and to test the hypothesis that dysregulation of protein kinases in the livers of AH patients may lead to liver failure and unresponsiveness to corticosteroid therapy.
Specific aims will include 1) creating a centralized facility for collecting human samples from patients with severe alcoholic hepatitis to make them available for our own research program as well as to any investigators requesting them; 2) generating transcriptome and proteome databases from liver tissues in patients with severe alcoholic hepatitis to make them available to alcohol research community for hypothesis generation; and 3) identifying therapeutic targets for AH patients through protein kinase analysis and providing these data to committed investigators for translational research.
s Alcoholic hepatitis is frequently a severe clinical condition associated with high short-term mortality. Research in this field has been hampered by both the absence of an appropriate animal model and the lack of readily availablehuman liver samples to conduct translational investigations in patients with severe alcoholic hepatitis. Creating a centralized facility to collect and share clinical samples and data relevant to the study of severe alcoholic hepatitis with committed investigators will promote discovery in this field.
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| Khanova, Elena; Wu, Raymond; Wang, Wen et al. (2018) Pyroptosis by caspase11/4-gasdermin-D pathway in alcoholic hepatitis in mice and patients. Hepatology 67:1737-1753 |
| Chao, Xiaojuan; Wang, Shaogui; Zhao, Katrina et al. (2018) Impaired TFEB-Mediated Lysosome Biogenesis and Autophagy Promote Chronic Ethanol-Induced Liver Injury and Steatosis in Mice. Gastroenterology 155:865-879.e12 |
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