Biomarkers of Disease in Alcoholic Hepatitis

酒精性肝炎疾病的生物标志物

• 批准号: 10190741
• 负责人: Gyongyi Szabo
• 金额: $ 26.12万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190741
• 关键词: Address; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholic beverage heavy drinker; Alcohols; B-Lymphocytes; Bacterial DNA; Biological; Biological Markers; Biological Response Modifiers; Biological Testing; CD8B1 gene; CSF3 gene; Cells; Characteristics; Clinical; Clinical Data; Clinical Trials; Complement; Control Groups; Dendritic Cells; Development; Disease; Elements; Evaluation; Frequencies; Goals; Host Defense; Immune; Immune response; Immunity; Immunologics; Immunosuppression; Impairment; Infection; Inflammasome; Inflammation; Inflammatory; Innate Immune Response; Interleukin-1 Receptors; Intervention; Intestinal permeability; Investigational Therapies; Leaky Gut; Link; Liver; Liver Regeneration; Liver diseases; Macrophage Activation; Molecular; Multiple Organ Failure; Myelogenous; Natural History; Observational Study; Organ; Organ failure; Outcome; Pathogenesis; Patients; Pattern; Peripheral Blood Mononuclear Cell; Phase; Phenotype; Population; Population Control; Precipitating Factors; Prednisone; Regenerative capacity; Regulatory T-Lymphocyte; Research Project Grants; Sampling; Sepsis; Serum; Signal Transduction; Systemic Inflammatory Response Syndrome; T-Lymphocyte; Testing; Translational Research; Zinc; anakinra; bench to bedside; biomarker discovery; circulating biomarkers; design; experimental study; immune activation; in vivo; insight; liquid biopsy; metabolomics; monocyte; mortality; neutrophil; novel; novel therapeutics; pathogen; pathogenic bacteria; pathogenic fungus; pathogenic virus; patient population; peripheral blood; problem drinker; prospective; research study; response; systemic inflammatory response; tool; treatment arm

ABSTRACT Alcoholic hepatitis (AH) is the most severe form of alcohol-induced organ damage in the liver with clinical manifestations of severe liver disease and high mortality. The precipitating factors and determinants of clinical outcome remain elusive in AH. The clinical outcome of AH depends on key factors such as 1) impaired host defense in the alcoholic patient that predisposes to infections; 2) systemic inflammation in AH that contributes to the development of Systemic Inflammatory Response Syndrome (SIRS) and multi-organ failure; and 3) the regenerative capacity of the liver. In this proposal, we aim to answer critical questions related to these key determinants of clinical outcomes using bedside to bench approaches. We will utilize biospecimens prospectively collected in the AlcHepNet clinical trial in the observational study (Aim#1) to evaluate the functional, phenotypic and metabolomics characteristics of major circulating immune cell populations in the well-defined patient populations in this study: severe AH, moderate AH, heavy drinkers without evidence of clinical liver disease, and normal control. Samples from the Late Stage Clinical Trial that include the treatment arms of prednisone, IL- 1receptor antagonist (IL-1ra, also known as anakinra, plus zinc) and G-CSF will be utilized to gain mechanistic insights into these novel treatments through translational research. Because these interventions target elements of inflammation, immune responses and/or liver regeneration, evaluation of the prospectively collected biospecimens will provide a valuable tool for mechanistic ex vivo studies that complement the clinical observations collected in the main clinical trial. The AlcHepNet clinical trial will collect clinical data on well-defined patient and control populations linked with unique biospecimens to support high-quality translational research and address some of the most burning clinical questions in AH. The Specific Aims are: Aim #1: To assess alcohol-induced immunosuppression and dysregulated innate immune responses to pathogen-derived signals in relation to the natural history, infections and clinical outcomes in patients with AH using samples from the AlcHepNet Observational Study. Aim #2: To test the biological consequences of novel therapies with IL-1ra and G-CSF on innate immune activation, markers of gut leakiness and circulating markers of liver regeneration using prospectively collected samples from the AlcHepNet Late Stage Clinical Trial. ! !

抽象的 酒精性肝炎（AH）是酒精引起的肝脏器官损伤最严重的形式，临床上有 严重肝病的表现和高死亡率。临床症状的诱发因素和决定因素 AH 的结果仍然难以捉摸。 AH 的临床结果取决于关键因素，例如 1) 宿主受损 酗酒者容易感染的防御； 2) AH 中的全身炎症导致 全身炎症反应综合征（SIRS）和多器官衰竭的发展； 3） 肝脏的再生能力。在本提案中，我们旨在回答与这些关键相关的关键问题 使用床边到工作台方法的临床结果的决定因素。我们将前瞻性地利用生物样本 在观察性研究 (Aim#1) 的 AlcHepNet 临床试验中收集，以评估功能、表型 明确患者中主要循环免疫细胞群的代谢组学特征 本研究中的人群：重度 AH、中度 AH、没有临床肝病证据的重度饮酒者，以及 正常控制。来自后期临床试验的样本，包括泼尼松、IL-的治疗组 1 受体拮抗剂（IL-1ra，也称为阿那白滞素，加锌）和 G-CSF 将用于获得机制 通过转化研究深入了解这些新颖的治疗方法。因为这些干预措施针对的是要素 炎症、免疫反应和/或肝再生、前瞻性收集的评估 生物样本将为机制离体研究提供一个有价值的工具，以补充临床研究 在主要临床试验中收集的观察结果。 AlcHepNet 临床试验将收集明确定义的临床数据 将患者和对照人群与独特的生物样本联系起来，以支持高质量的转化研究 并解决 AH 中一些最紧迫的临床问题。具体目标是： 目标#1：评估酒精引起的免疫抑制和失调的先天免疫反应 与患者自然史、感染和临床结果相关的病原体衍生信号 使用来自 AlcHepNet 观察研究的样本进行 AH 分析。 目标#2：测试 IL-1ra 和 G-CSF 新疗法对先天免疫的生物学影响 前瞻性地使用激活、肠渗漏标志物和肝再生循环标志物 从 AlcHepNet 后期临床试验中收集样本。 ！ ！