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.

项目概要 酒精性肝炎（AH）是酒精性肝病（ALD）的急性表现，通常预后很差。 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，而且 大约一半的患者在短时间内仍然死亡。急性研究中一个未满足的主要需求 酒精性肝炎缺乏可靠的动物模型来模拟该疾病的整个谱系 人类。因为基于人类样本的转化研究对于理解 酒精性肝炎的机制，从严重 AH 患者身上收集生物标本可能会有所帮助 实质上是在设计新的治疗策略。由于大多数 AH 死亡发生在发病后 2 个月内， 早期肝移植很有吸引力，但也存在争议，因为历史上要求 6 个月 戒酒。 2012 年，根据法国的报告，我们开始了一项移植计划 约翰·霍普金斯大学的急性 AH 患者已进行 20 例此类移植，一年生存率为 95%， 结果类似于或优于 NEJM 中报道的结果。由于很少有其他中心，而且我们地区没有一个 我们是 AH 患者的区域转诊中心，负责处理这些病例。同样，当这些患者 接受肝移植时，会进行自体肝切除术，并将移植的肝脏作为 研究 AH 的不寻常资源。为了促进该领域的创新和转化研究，我们正在 寻求支持以开发服务于酒精研究的严重酒精性肝炎临床资源 社区。借助 R24 支持，我们将在治疗期间收集严重 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， 移植物中的肝星状细胞、库普弗细胞、肝窦内皮细胞和浸润淋巴细胞 肝。约翰·霍普金斯医院生物保存专家的支持将提供适当的帮助 样品处理和储存确保实验结果的质量。我们将建立一个集中的数据库 去识别化的样本，以促进获取原本无法获得的样本， 协作、效率和治愈进展。与高通量专家合作 约翰霍普金斯大学生物中心，我们还将利用该资源进行转录组和蛋白质组研究 分析并检验 AH 患者肝脏中蛋白激酶失调可能导致的假设 肝功能衰竭和对皮质类固醇治疗无反应。具体目标包括 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的设施，以便将其用于 我们自己的研究计划以及任何提出要求的研究人员； 2) 生成转录组和 来自严重酒精性肝炎患者肝组织的蛋白质组数据库，使它们可用于 酒精研究团体的假设生成； 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。