Clinical Resources for Alcoholic Hepatitis Investigations

酒精性肝炎研究的临床资源

• 批准号: 9982730
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982730
• 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）是经常具有严重预后的酒精性肝病（ALD）的急性表现。 尽管皮质类固醇治疗对短期生存的积极影响，但这种治疗并不理想，并且 短时间后，大约一半的患者仍然死亡。急性研究的主要未满足需要 酒精性肝炎是缺乏可靠的动物模型，该模型模仿了这种疾病的整个谱系 人类。因为基于人类样本的翻译研究在理解中具有关键作用 酒精性肝炎的机制，来自严重AH患者的生物标本的收集可能有助于 在设计新的治疗策略方面基本上是在设计中。由于大多数AH死亡发生在发病后2个月内 早期肝移植具有吸引力，但由于历史性6个月而引起争议 戒酒。在法国报告之后，2012年，我们开始了一项移植计划 约翰·霍普金斯（Johns Hopkins）患有急性AH的患者，并进行了20种此类移植，其生存率为95％， 结果与NEJM中报道的结果相似或优越。正如其他几个中心，我们地区没有的中心是 承担这些案例，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，进行天然肝切除术，其外植物肝脏作为一个 AH研究的不寻常资源。为了促进该领域的创新和转化研究，我们是 寻求支持以开发严重酒精性肝炎的临床资源，该资源为酒精研究服务 社区。有了R24的支持，我们将收集来自严重AH患者的肝脏和数据 从供体肝脏作为对照的移植和楔形活检。具体而言，我们将隔离肝细胞， 肝星细胞，kupffer细胞，正弦内皮细胞和浸润的淋巴细胞 肝。约翰霍普金斯医院的生物保护专家的支持将为适当的 样品处理和存储以确保质量实验结果。我们将建立一个集中式数据库 取消识别的样品的目的是促进访问其他不可用的标本， 协作，效率和进步朝着治愈方向发展。与高吞吐量的专家合作 约翰·霍普金斯（Johns Hopkins）的生物学中心，我们还将利用此资源来执行转录组和蛋白质组 分析并检验以下假设：AH患者肝脏中蛋白激酶的失调可能导致 肝衰竭和对皮质类固醇治疗的反应。具体目标包括1）创建集中式 用于从严重酒精性肝炎患者那里收集人类样品的设施，以使其可用 我们自己的研究计划以及任何要求他们的调查人员； 2）生成转录组和 严重酒精性肝炎患者的肝组织的蛋白质组数据库，使其可用 假设产生的酒精研究界； 3）确定AH患者的治疗靶标 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者。