Clinical Resources for Alcoholic Hepatitis Investigations

项目摘要 酒精性肝炎(AH)是酒精性肝病(ALD)的一种急性表现，通常预后严重。 尽管皮质类固醇治疗对短期生存有积极作用，但这种治疗方法并不理想。 大约一半的患者在短时间后仍会死亡。急性胰腺炎研究中一个尚未得到满足的主要需求 酒精性肝炎是缺乏一种可靠的动物模型来模拟这种疾病的整个谱系 人类。因为基于人体样本的翻译研究在理解 酒精性肝炎的机制，收集重型肝炎患者的生物标本可能会有所帮助 在设计新的治疗策略方面有很大的帮助。由于大多数急性呼吸道感染死亡发生在发病后2个月内， 早期肝移植很有吸引力，但也有争议，因为历史上要求移植6个月 戒酒戒酒。2012年，在法国的报告之后，我们开始了一个移植计划 约翰霍普金斯大学的急性急性肝炎患者，已经进行了20次这样的移植，1年存活率为95%， 结果与《新英格兰医学杂志》报道的结果相似或更好。因为很少有其他中心，在我们地区没有一个是 承担这些病例，我们是一个地区转诊中心，为急性肝炎患者。同样，当这些患者 接受肝移植时，施行自体肝切除，移植的肝脏作为 不寻常的研究资源。为了促进这一领域的创新和翻译研究，我们正在 寻求支持开发为酒精研究服务的重型酒精性肝炎临床资源 社区。有了R24的支持，我们将收集严重急性肝炎患者的肝脏和数据 移植，并取供肝楔形活检作为对照。具体地说，我们将分离肝细胞， 肝星状细胞、枯否细胞、肝窦内皮细胞和浸润性淋巴细胞 肝脏。约翰霍普金斯医院生物保护专家的支持将在适当的情况下提供帮助 样品的处理和保存，确保实验结果的质量。我们将建立一个集中的数据库 为了促进获取其他方面无法获得的样本， 协作、效率和进步，朝着治愈的方向前进。与来自高吞吐量的专家合作 在约翰·霍普金斯大学生物中心，我们还将利用这一资源进行转录和蛋白质组学 分析和检验肝组织蛋白激酶调节失调可能导致肝纤维化的假说 肝功能衰竭和对皮质类固醇治疗无反应。具体目标将包括1)创建一个集中的 从严重酒精性肝炎患者身上采集人体样本以供临床使用的设备 我们自己的研究计划以及任何提出要求的调查人员；2)生成转录组和 重型酒精性肝炎患者肝组织蛋白质组数据库 用于假设生成的酒精研究社区；以及3)确定AH患者的治疗靶点 通过蛋白激酶分析，并将这些数据提供给致力于翻译研究的研究人员。

Project Summary 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.