Biomarkers of Disease in Alcoholic Hepatitis

酒精性肝炎疾病的生物标志物

• 批准号: 10020707
• 负责人: Gyongyi Szabo
• 金额: $ 22.36万
• 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/10020707
• 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; Failure; 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; Myelogenous; Natural History; Observational Study; Organ; Organ failure; Outcome; Pathogenesis; Patients; Pattern; Peripheral Blood Mononuclear Cell; Phase; Phenotype; Population; Population Control; Precipitating Factors; Prednisone; 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; regenerative; research study; 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）是肝脏中酒精诱导的器官损伤最严重的形式 严重肝病和高死亡率的表现。临床的沉淀因子和决定因素 结果在AH中仍然难以捉摸。 AH的临床结果取决于关键因素，例如1）宿主受损 含有易感感染的酒精患者的防御； 2）AH的系统性炎症有助于 系统性炎症综合征（SIR）和多器官失败的发展； 3） 肝脏再生能力。在此提案中，我们旨在回答与这些关键有关的关键问题 使用床边到板凳方法的临床结果的决定因素。我们将前瞻性地利用生物测量 在观察性研究（AIM＃1）中收集的藻类临床试验中，以评估功能，表型 定义明确的患者中主要循环免疫细胞种群的代谢组学特征 这项研究中的人群：严重的AH，中度AH，没有临床肝病证据的重量饮酒者， 正常控制。晚期临床试验的样品包括泼尼松的治疗组，IL- 1拮抗剂（IL-1RA，也称为Anakinra，以及锌），将使用G-CSF来获得机械 通过转化研究深入了解这些新颖的治疗方法。因为这些干预措施目标要素 炎症，免疫反应和/或肝脏再生，对前瞻性收集的评估 生物测量将为机械性离体研究提供有价值的工具，以补充临床 在主要临床试验中收集的观察结果。 Alchepnet临床试验将收集定义明确的临床数据 患者和控制人群与独特的生物测量有关，以支持高质量的转化研究 并解决AH中一些最燃烧的临床问题。具体目的是： 目的1：评估酒精引起的免疫抑制和对先天免疫反应的失调 病原体衍生的与自然病史，感染和临床结局有关的信号 使用AH使用ALCHEPNET观察性研究的样品。 目标＃2：测试使用IL-1RA和G-CSF对先天免疫的新型疗法的生物学后果 激活，肠道泄漏的标记和前瞻性的肝脏再生循环标记 从Alchepnet后期临床试验中收集了样品。 呢 呢