Clinical Resources for Alcoholic Hepatitis Investigations

酒精性肝炎研究的临床资源

• 批准号: 9754728
• 负责人: ZHAOLI SUN
• 金额: $ 61万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754728
• 关键词: Acute; Acute Alcoholic Hepatitis; Adrenal Cortex Hormones; Alcoholic Hepatitis; Alcoholic Liver Diseases; Animal Model; Biology; Biopsy; Catalogs; Cessation of life; Cholestasis; Cirrhosis; Clinical; Collaborations; Collection; Communities; Data; Data Set; Databases; Development; Discontinuous Capillary; Disease; Endothelial Cells; Ensure; Ethanol; Ethanol Metabolism; Fibrosis; Funding; Gene Proteins; Generations; Goals; Hepatectomy; Hepatic Stellate Cell; Hepatocellular Damage; Hepatocyte; Hospitals; Human; Inflammation; Investigation; Journals; Knowledge; Kupffer Cells; Lead; Liver; Liver Failure; Liver diseases; Lymphocyte; Medical; Medicine; Modeling; Molecular; Monoclonal Antibody R24; Mouse Strains; National Institute on Alcohol Abuse and Alcoholism; New England; Pathogenesis; Pathology; Patients; Peripheral Blood Mononuclear Cell; Phosphorylation; Phosphotransferases; Plasma; Protein Kinase; Proteome; Proteomics; Publishing; Reaction; Reporting; Research; Research Personnel; Research Project Grants; Resources; Rodent; Sampling; Series; Serum; Signal Pathway; Signal Transduction; Specimen; Supportive care; Testing; Time; Tissues; Translational Research; Transplant Recipients; Transplantation; United Network for Organ Sharing; Whole Blood; Work; alcohol abstinence; alcohol research; base; biomedical referral center; cell type; central database; comparative; data mining; design; differential expression; experience; feeding; human data; human tissue; improved; innovation; liver inflammation; liver injury; liver transplantation; mortality; new therapeutic target; novel therapeutic intervention; outcome forecast; preservation; programs; therapeutic target; transcriptome; translational scientist; transplant centers

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.

项目摘要 酒精性肝炎（AH）是酒精性肝病（ALD）的急性表现，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，但这种治疗并不理想， 大约一半的患者在短时间内死亡。急性脑梗死研究中的一个主要未满足的需求是 酒精性肝炎是缺乏一个可靠的动物模型，模仿这种疾病的整个频谱， 人类因为基于人类样本的转化研究在理解 酒精性肝炎的发病机制，从重度AH患者中收集生物标本可能有助于 在新的治疗策略的设计中发挥重要作用。由于大多数AH死亡发生在发病后2个月内， 早期肝移植是有吸引力的，但由于历史上要求6个月， 戒酒2012年，在法国的报告之后，我们开始了一项移植计划， 在约翰霍普金斯的急性AH患者中进行了20例这样的移植，1年存活率为95%， 结果与NEJM中报道的结果相似或上级。因为很少有其他中心，我们地区没有一个中心 我们是AH患者的区域转诊中心。同样，当这些患者 接受肝移植，进行自体肝切除术，切除的肝脏作为 不寻常的资源为研究AH。为了促进该领域的创新和转化研究，我们 寻求支持，开发服务于酒精研究的重型酒精性肝炎临床资源 社区有了R24的支持，我们将在研究期间收集严重AH患者的肝脏和数据。 移植和来自供体肝脏的楔形活检作为对照。具体来说，我们将分离肝细胞， 肝星状细胞、枯否细胞、血窦内皮细胞和浸润淋巴细胞 肝脏约翰霍普金斯医院的生物保存专家将提供适当的帮助， 样品处理和储存，以确保实验结果的质量。我们将建立一个集中的数据库 去识别样本，以促进获取其他不可用的标本， 合作、效率和治疗进展。在与来自高收入国家的专家合作下， 生物中心在约翰霍普金斯，我们也将利用这一资源进行转录组和蛋白质组 分析并检验AH患者肝脏中蛋白激酶失调可能导致 肝衰竭和对皮质类固醇治疗无反应。具体目标包括：1）建立一个集中的 从重度酒精性肝炎患者身上采集人体样本的设施， 我们自己的研究计划，以及任何调查人员要求他们; 2）产生转录组， 从重度酒精性肝炎患者肝组织中提取蛋白质组数据库，使其可用于 酒精研究社区的假设生成;和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转化研究的研究人员。