Extracellular Vesicles in Alcoholic Liver Disease: Basic and Pre-Clinical Discovery

酒精性肝病中的细胞外囊泡：基础和临床前发现

• 批准号: 10208640
• 负责人: Gyongyi Szabo
• 金额: $ 43.56万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208640
• 关键词: Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholic beverage heavy drinker; Alcohols; Biogenesis; Biological Markers; Biological Process; Biology; Caliber; Cells; Characteristics; Chronic; Clinical; Code; Data; Diagnosis; Disease; Disease Outcome; Future; Hepatitis B; Hepatocyte; Hepatology; Human; Immune; Infection; Inflammation; Literature; Liver diseases; Mass Spectrum Analysis; Mediator of activation protein; MicroRNAs; Observational Study; Organ; Outcome; Patients; Phase; Pilot Projects; Population; Preparation; Prognosis; Proteins; Proteomics; Protocols documentation; Quality Control; RNA; RNA purification; Research Personnel; Research Project Grants; Resources; Sampling; Serum; Source; Translational Research; Untranslated RNA; Whole Blood; alcohol exposure; alcohol research; base; biomarker discovery; biomarker signature; candidate marker; clinical application; cohort; disease natural history; exosome; extracellular vesicles; insight; large datasets; liver injury; microvesicles; mortality; novel marker; potential biomarker; pre-clinical; predict clinical outcome; problem drinker; protein biomarkers; protein purification; tool; transcriptome; transcriptome sequencing; transcriptomics; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholic beverage heavy drinker; Alcohols; Biogenesis; Biological Markers; Biological Process; Biology; Caliber; Cells; Characteristics; Chronic; Clinical; Code; Data; Diagnosis; Disease; Disease Outcome; Future; Hepatitis B; Hepatocyte; Hepatology; Human; Immune; Infection; Inflammation; Literature; Liver diseases; Mass Spectrum Analysis; Mediator of activation protein; MicroRNAs; Observational Study; Organ; Outcome; Patients; Phase; Pilot Projects; Population; Preparation; Prognosis; Proteins; Proteomics; Protocols documentation; Quality Control; RNA; RNA purification; Research Personnel; Research Project Grants; Resources; Sampling; Serum; Source; Translational Research; Untranslated RNA; Whole Blood; alcohol exposure; alcohol research; base; biomarker discovery; biomarker signature; candidate marker; clinical application; cohort; disease natural history; exosome; extracellular vesicles; insight; large datasets; liver injury; microvesicles; mortality; novel marker; potential biomarker; pre-clinical; predict clinical outcome; problem drinker; protein biomarkers; protein purification; tool; transcriptome; transcriptome sequencing; transcriptomics

ABSTRACT Alcoholic hepatitis (AH) has high mortality and management of these patients is limited by the lack of reliable markers of liver injury, inflammation and infection that determine clinical outcomes. Extracellular vesicles (EVs) are novel biomarkers that are more sensitive compared to serum associated-biomarkers because of the stability of biomolecules within the EVs. EVs contain characteristic RNA and protein cargo that can provide a unique signature of disease. While characterization of these different EV populations is an emerging field, the use of EVs as potential biomarkers is rapidly evolving in clinical applications. Our preliminary results suggest that there is an increased number of EVs in AH and these EVs have distinct RNA, micro-RNA and protein cargos compared to normal controls that indicate their potential for biomarker discovery. However, the features of biology that distinguish heavy drinkers with no liver disease from those who present with alcoholic hepatitis are unknown. In this application, we propose to take a two-step approach to study the EV cargo as a potential biomarker in alcoholic hepatitis. The UH2 phase will focus on the discovery phase in two steps: first, to define optimal approaches to EV isolation, RNA and protein sample preparation and, second, pilot proteomics and transcriptome analyses that will identify potential biomarker candidates in alcoholic hepatitis compared to normal controls (DASH samples). The second, UH3, phase will validate the proteomic and RNA-seq characteristic of EVs from the UH2 phase now in a larger cohort of AH patients from the AlcHepNet Observational study and compare those to heavy drinkers (HD) without liver disease (discovery). Proteomic and RNA transcriptomic profiles of the 3 sets of well-characterized human cohorts will identify EV-associated signatures of AH that is different from HD without liver disease and normal controls. Our study will further discover correlations between unique signatures in the protein cargo and/or RNA transcriptome profile of EVs that indicate survival and/or clinical outcomes in AH. The large dataset from these “omics” analyses will establish a unique AH-proteomic-transcriptome interface (AH-PTI) and this will provide invaluable resources for the AlcHepNet investigators and the entire alcohol research field for future hypothesis-driven studies.

抽象的 酒精性肝炎（AH）的死亡率很高，这些患者的治疗受到缺乏可靠的限制 决定临床结果的肝损伤，感染和感染的标志物。细胞外蔬菜（EV） 与血清相关的生物标志物相比，是新颖的生物标志物，因为 电动汽车内生物分子的稳定性。电动汽车包含特征性RNA和蛋白质货物，可以提供 疾病的独特签名。尽管这些不同的EV群体的表征是一个新兴领域，但 在临床应用中，将电动汽车用作潜在的生物标志物正在迅速发展。我们的初步结果表明 AH中的电动汽车数量增加，这些EV具有不同的RNA，微RNA和蛋白质 与表明其生物标志物发现潜力的正常对照相比，赤符。但是，功能 生物学，将没有肝病的重量饮酒与患有酒精性肝炎的人区分开 是未知的。在此应用中，我们建议采用两步方法来研究EV货物作为潜力 酒精性肝炎中的生物标志物。 UH2阶段将以两个步骤重点关注发现阶段：首先，定义 最佳的EV隔离，RNA和蛋白质样品制备方法，其次是pilot蛋白质组学和 转录组分析将确定酒精性肝炎中潜在的生物标志物候选者 正常对照（仪表样本）。第二个UH3相将验证蛋白质组学和RNA-seq 现在，来自UH2阶段的电动汽车的特征在较大的AL Chepnet的AH患者中 观察性研究并将其与没有肝病的重饮酒者（HD）进行比较（发现）。蛋白质组学 和三组良好的人类人群的RNA转录组曲线将确定与EV相关的 AH的特征与没有肝病和正常对照的HD不同。我们的研究将进一步 发现蛋白质货物中唯一特征与/或电动汽车的RNA转录组曲线之间的相关性 这表明AH中的生存和/或临床结果。这些“ OMIC”分析的大数据集将 建立独特的AH蛋白质转录组接口（AH-PTI），这将为您提供宝贵的资源 藻类研究者和整个酒精研究领域，用于未来假设驱动的研究。