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Translational Bioenergetics in Patients with Alcoholic Liver Disease

酒精性肝病患者的转化生物能学

基本信息

批准号：
9061506
负责人：
VICTOR M DARLEY-USMAR
金额：
$ 17.46万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9061506
关键词：
Acute Acute Alcoholic Hepatitis Admission activity Adrenal Cortex Hormones Aftercare Alcohol consumption Alcoholic Hepatitis Alcoholic Liver Cirrhosis Alcoholic Liver Diseases Animal Model Basic Science Bioenergetics Biological Markers Biometry Blood Blood Cells Blood Platelets Blood Tests Blood specimen Cell Count Cell Death Characteristics Chronic Cirrhosis Clinical Clinical Trials Data Decision Making Defect Depressed mood Development Diagnosis Disease Effectiveness Ethanol toxicity Evaluation Exhibits Fever Functional disorder Gastrointestinal Hemorrhage Generations Health Hepatic Hepatitis Hepatomegaly Human Hyperglycemia Icterus Infection Inflammation Intervention Leukocytes Leukocytosis Liver Liver Failure Measurement Metabolic Metabolic stress Methodology Methods Mitochondria NADPH Oxidase Organ Oxidative Stress Pathogenesis Pathology Patients Pentoxifylline Pharmaceutical Preparations Reactive Oxygen Species Recruitment Activity Reporting Respiratory Burst Risk Sampling Sepsis Syndrome Severities Steroid Resistance Steroids Stress Syndrome Testing Time Toxic effect accurate diagnosis base high throughput screening individual patient liver biopsy mitochondrial dysfunction monocyte mortality neutrophil non-alcoholic novel novel marker novel therapeutic intervention potential biomarker predictive marker problem drinker public health relevance research clinical testing response tool

项目摘要

DESCRIPTION (provided by applicant): Alcoholic hepatitis is a syndrome characterized by rapid onset of jaundice, liver failure and the key features of a systemic inflammatory response syndrome. Patients with severe episodes of alcoholic hepatitis have a mortality rate as high as 40-50% 1 month after presentation. The treatment of acute alcoholic hepatitis is a clinical challenge because a) it is difficult to differentiate it from spontaneous decompensation of alcoholic cirrhosis and b) the limited treatment options have variable and unpredictable efficacy. Furthermore, currently- available treatments for alcoholic hepatitis patients with corticosteroids or pentoxifylline provide only about 50% survival benefit. Hence, there is an unmet need of a biomarker for diagnosis of alcoholic hepatitis and predicting its responsiveness to treatment with corticosteroids. Basic research into the pathogenesis of alcoholic liver disease using animal models has identified a number of contributory factors including inflammation, mitochondrial dysfunction and a severe oxidative/nitrative stress. An intrinsic characteristic of pathologies associated with inflammation and metabolic dysfunction is the suppression of the cellular bioenergetics to below the threshold that induces cell death. In this proposal, we will use a novel methodology to assess cellular bioenergetics in the leukocytes isolated from patient's blood and test the hypothesis that this can serve as a biomarker of the severity of alcoholic liver disease. This project builds on the expertise of the PIs in managing alcoholic liver disease patients, biostatistics and the evaluation of mitochondrial dysfunction in disease. We have found that a) bioenergetic health can be defined by an analysis of cellular bioenergetics in blood leukocytes that can be isolated from 20 ml of human blood, b) monocytes show a rapidly developing decrease in bioenergetic health in patients with alcoholic liver disease, and c) the oxidative burs in neutrophils and monocytes can be readily assessed in the same sample and is depressed in alcoholic patients. In this application we will test the hypothesis that alcoholic liver disease patients with severe cellular bioenergetic defects and low oxidative burst activity detectable in monocytes and neutrophils will progress more rapidly to liver failure and be unresponsive to corticosteroid treatment.

描述（由申请人提供）：酒精性肝炎是一种以快速出现黄疸、肝功能衰竭和全身炎症反应综合征为主要特征的综合征。严重酒精性肝炎患者发病后1个月死亡率高达40-50%。急性酒精性肝炎的治疗是一项临床挑战，因为：a）很难将其与酒精性肝硬化的自发失代偿区分开来；b）有限的治疗选择具有可变且不可预测的疗效。此外，目前使用皮质类固醇或己酮可可碱治疗酒精性肝炎患者仅能提供约50%的生存获益。因此，用于诊断酒精性肝炎并预测其对皮质类固醇治疗的反应的生物标志物的需求尚未得到满足。使用动物模型对酒精性肝病发病机制进行的基础研究已经确定了许多促成因素，包括炎症、线粒体功能障碍和严重的氧化/硝化应激。与炎症和代谢功能障碍相关的病理学的一个内在特征是将细胞生物能量抑制到诱导细胞死亡的阈值以下。在这个提案中，我们将使用小说评估从患者血液中分离出的白细胞的细胞生物能学的方法，并测试其可以作为酒精性肝病严重程度的生物标志物的假设。该项目建立在 PI 在管理酒精性肝病患者、生物统计学和疾病中线粒体功能障碍评估方面的专业知识之上。我们发现：a) 生物能健康状况可以通过对从 20 ml 人体血液中分离出来的白细胞的细胞生物能学进行分析来定义，b) 单核细胞在酒精性肝病患者中表现出生物能健康状况迅速下降，以及 c) 中性粒细胞和单核细胞中的氧化毛刺可以在同一样本中轻松评估，并且在酗酒者。在本申请中，我们将测试以下假设：具有严重细胞生物能缺陷和单核细胞和中性粒细胞中可检测到的低氧化爆发活性的酒精性肝病患者将更快地进展为肝衰竭并且对皮质类固醇治疗无反应。