Project 3-Proteomic Analysis of Explanted Livers with characterization of Autoantigens

项目 3 - 外植肝脏的蛋白质组学分析及自身抗原的表征

• 批准号: 10560561
• 负责人: Heng Zhu
• 金额: $ 32.55万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560561
• 关键词: ADCC Assay; Acceleration; Acute; Adaptive Immune System; Adrenal Cortex Hormones; Affect; Alcohol abuse; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Animal Model; Antibodies; Antibody Response; Antigens; Autoantibodies; Autoantigens; B-Lymphocytes; Bacteria; Bacterial Antigens; Bioinformatics; Biological Assay; Biopsy Specimen; Blood; Cell Separation; Cells; Chronic; Circulation; Cross Reactions; Deposition; Development; Diagnosis; Disease; Escherichia coli; Etiology; Generations; Goals; HIV; HIV/HCV; Hepatitis C virus; Hepatocyte; Human; IgE; Immunofluorescence Immunologic; Immunoglobulin A; Immunoglobulin G; Immunoglobulins; Immunohistochemistry; Individual; Infection; Inflammation; Inflammatory; Injury; Liver; Liver diseases; Microarray Analysis; Modeling; Molecular; Mycobacterium tuberculosis; Patients; Pneumonia; Predisposition; Prevention; Production; Protein Microchips; Proteins; Proteome; Proteomics; Relapse; Research Personnel; Sampling; Serum; Stains; T-Lymphocyte; Testing; Therapeutic Intervention; Tissues; Transplant Recipients; Transplantation; Tuberculosis; Virus Diseases; alcohol relapse; chronic alcohol ingestion; cohort; cytokine; expectation; gut bacteria; human model; interdisciplinary approach; liver allograft; liver biopsy; liver injury; liver transplantation; mortality; new therapeutic target; novel therapeutics; oxidative damage; relapse patients

PROJECT SUMMARY Severe alcoholic hepatitis (SAH) is the most severe form of the alcoholic liver diseases (ALD). Chronic alcohol abuse is associated with increased susceptibility to pneumonia, infections (e.g., HIV, HCV, and Tuberculosis), and with chronic inflammation. Studies in the past thirty years in both humans and animal models revealed that ALD is likely caused by impact of alcohol abuse on adaptive immune system. Chronic alcohol abuse was found to reduce the number of B cells, decrease antigen-specific antibody responses, and increase the production of autoantibodies against liver autoantigens and byproducts of oxidative damage. Moreover, increased levels of immunoglobulin of IgG, IgA, and IgE isotypes and production of autoantibodies against liver antigens have been observed in patients with SAH. Therefore, we hypothesize that generation of autoantibodies in patients with SAH contributes to liver damage. To fully test this hypothesis, the identification of those antigens recognized by antibodies deposited in SAH livers is a crucial stepping-stone towards understanding the etiology of the diseases. In addition, it is likely that some of these antibodies are created from cross-reacting antibodies directed against bacteria in the gut. The goal of this proposal is to determine the origins of these SAH-specific antibodies in patients with SAH and characterize their function and contribution to liver damage. We will take full advantage of the biospecimens collected from the explanted livers of patients with SAH, as well as donor livers and livers diagnosed for other liver diseases, and employ the cutting-edge protein microarray technology to achieve four Specific Aims: 1) Identify autoantigens that are specifically recognized by antibodies extracted from explanted livers or blood of the patients with SAH; 2) Profile antibody signatures to bacterial antigens in patients with SAH; 3) Characterize functions of the antibodies extracted from SAH livers using a cell-based model; and 4) Examine whether alcohol abuse-induced autoantibodies cause liver allograft injury in alcohol relapse patients after liver transplantation. We believe that of this project will allow us to identify novel therapeutic targets and develop novel therapy for intervention and prevention of SAH.

项目摘要 严重的酒精性肝炎（SAH）是酒精性肝病（ALD）最严重的形式。慢性酒精 虐待与肺炎，感染（例如HIV，HCV和结核病）的易感性增加有关， 并患有慢性炎症。在过去的三十年中，在人类和动物模型中的研究表明， ALD可能是由于酗酒对自适应免疫系统的影响而引起的。发现慢性酒精滥用 为了减少B细胞的数量，减少抗原特异性抗体反应，并增加 针对肝自身抗原和氧化损伤的副产物的自身抗体。此外，增加了 IgG，IgA和IgA同种型的免疫球蛋白以及针对肝抗原的自身抗体的产生 在SAH患者中观察到。因此，我们假设患者的自身抗体产生 SAH会导致肝脏损害。为了充分检验这一假设，这些抗原的识别 通过沉积在SAH肝脏中的抗体识别是一个至关重要的垫脚石 疾病的病因。另外，这些抗体中的一些可能是通过交叉反应而产生的 针对肠道细菌的抗体。该提议的目的是确定这些的起源 SAH患者的SAH特异性抗体，表征其功能和对肝损害的贡献。 我们将充分利用从SAH患者的外植物肝脏中收集的生物测量，AS 以及因其他肝病诊断的供体肝脏和肝脏，并采用了尖端蛋白质 微阵列技术实现四个特定目标：1）识别特定认可的自动抗原 由SAH患者的肝肝或血液中提取的抗体； 2）概况抗体特征 SAH患者的细菌抗原； 3）表征从SAH肝提取的抗体的功能 使用基于细胞的模型； 4）检查酒精滥用引起的自身抗体是否引起同种异体移植 肝移植后酒精复发患者的损伤。我们相信这个项目将使我们能够 确定新颖的治疗靶标，并开发新的治疗疗法，以进行干预和预防SAH。