Liquid biopsy for alcoholic hepatitis: diagnosis, prognosis and technology development

酒精性肝炎液体活检：诊断、预后和技术开发

• 批准号: 9980231
• 负责人: Harmeet Malhi
• 金额: $ 24.58万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-20 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980231
• 关键词: Address; Alcoholic Hepatitis; Alcoholic Liver Diseases; Applications Grants; Bilirubin; Biological Assay; Biological Markers; Blood Circulation; Blood Tests; Cell Communication; Cells; Ceramides; Clinical; Clinical Trials; Cytoprotective Agent; Data; Derivation procedure; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Early Diagnosis; Ethanol; Event; Goals; Health Professional; Heavy Drinking; Hepatocyte; Human; International Normalized Ratio; Link; Liver; Liver diseases; Mass Spectrum Analysis; Measures; Mediating; Methods; Modeling; N-palmitoylsphingosine; Pathogenesis; Pathogenicity; Pathway interactions; Patient Care; Patients; Performance; Pharmacology; Plasma; Population; Pre-Clinical Model; Prognostic Marker; Prospective cohort; Reporting; Risk; Severities; Signal Pathway; Signal Transduction; Site; Sphingolipids; Standardization; Technology; Testing; Therapeutic Agents; Training; Validation; base; ceramide 1-phosphate; circulating biomarkers; clinical care; clinically relevant; cohort; diagnostic biomarker; effective therapy; extracellular vesicles; health care service utilization; improved; innovation; interleukin-22; liquid biopsy; liver inflammation; liver injury; macrophage; mortality; novel; novel diagnostics; outcome forecast; patient stratification; pilot trial; pre-clinical; predicting response; predictive marker; predictive signature; prognostic; prognostic tool; prospective; rapid diagnosis; recruit; research clinical testing; response; sphingosine 1-phosphate; survival prediction; technology development; therapeutic target; tool; vesicular release

PROJECT SUMMARY/ABSTRACT The long-term objective of this translational U01 is to define pathophysiologically informed and clinically relevant biomarkers based on the sphingolipidomic cargo of extracellular vesicles (EVs) that will serve for the diagnosis and prognosis of subjects with alcoholic hepatitis (AH). AH is the severest form of alcohol-induced liver disease with high mortality, high health care utilization, and the absence of effective therapies. Health care professionals are limited by the lack of predictive and prognostic biomarkers that could risk-stratify AH patients and individualize their therapy based on biomarker profiles. The current proposal links hepatocyte-derived sphinogolipid cargo on EVs to macrophage-mediated liver inflammation by proposing that sphingolipids on EVs from ethanol-damaged hepatocytes recruit macrophages in to the liver, resulting in liver injury and inflammation. Our preliminary data show that EVs are elevated in AH with the following features: i) EV sphingolipids are elevated in AH; ii) EV sphingolipid levels correlate with clinical parameters such as the international normalized ratio, bilirubin, and MELD score; iii) EVs activate proinflammatory macrophage effector responses via sphingolipid signaling; and iv) Hepatocyte-derived EVs can be detected via a novel nanoplasmon enhanced scattering (nPES) assay. This has led to the central hypothesis that circulating EV sphingolipid cargo is a pathogenically relevant biomarker for the diagnosis and prognosis of AH. Therefore, the goals of this proposal are to: i) develop an EV sphingolipidomic diagnostic signature for AH; ii) Demonstrate the ability of EV sphingolipidomics to predict mortality in AH; iii) Extend EV sphingolipidomics to a “proof-of-mechanism” assay for the beneficial effects observed in AH patients treated with therapeutic agents proposed in our linked complementary Clinical Trial Pilot U01 (RFA-AA-18-005); and iv) Develop a novel clinical test for the diagnosis of AH utilizing nPES technology to diagnose AH by detecting hepatocyte-derived EVs in plasma microsamples. First, we will determine the diagnostic performance of EV sphingolipids for AH in a single-site training cohort followed by a multi-site validation cohort. Second, we will directly test the hypothesis that EV sphingolipids can predict survival and response to a therapy that is expected to reduce the release of EVs from hepatocytes. Third, we will develop and validate a novel clinical assay for the diagnosis of AH. Thus, this multi-PI U01 grant application will yield a liquid biopsy biomarker for AH diagnosis and prognosis.

项目摘要/摘要 这种翻译U01的长期目标是定义病理生理知识和临床知识 相关的生物标志物基于细胞外蔬菜（EV）的鞘脂组货物（EV） 酒精性肝炎受试者（AH）的诊断和预后。 AH是酒精引起的最严重形式 肝病死亡率高，医疗保健利用率高以及缺乏有效的疗法。卫生保健 专业人士受到缺乏预测性和预后生物标志物的限制 并基于生物标志物概况来个性化疗法。当前的提案链接肝细胞衍生 通过提出EV上的鞘脂，在电动汽车到巨噬细胞介导的肝脏注射到巨噬细胞介导的肝脏注射 从乙醇受损的肝细胞招募巨噬细胞到肝脏，导致肝损伤和 炎。我们的初步数据显示，EV在AH中具有以下功能：i）EV 鞘脂在AH中升高； ii）EV鞘脂水平与临床参数（例如 国际标准化比率，胆红素和MELD得分； iii）电动汽车激活促炎巨噬细胞 通过鞘脂信号传导的效应子响应；和iv）可以通过小说检测到肝细胞衍生的电动汽车 纳米群增强散射（NPE）分析。这导致了循环ev的中心假设 鞘脂货物是AH诊断和预后的病原体相关生物标志物。 因此，该提案的目标是：i）为AH开发EV鞘脂组诊断签名； ii） 证明EV鞘脂型理学预测AH死亡率的能力； iii）将EV鞘脂组学扩展到 在接受治疗剂治疗的AH患者中观察到的有益作用的“机制证明”测定法 在我们链接的完整临床试验PILOT U01（RFA-AA-18-005）中提出了提议；和iv）发展小说 使用NPES技术诊断AH的临床测试通过检测肝细胞衍生来诊断AH 血浆微观样本中的电动汽车。首先，我们将确定AH的EV鞘脂的诊断性能 一个单位训练队列，然后进行多站点验证队列。第二，我们将直接测试 EV鞘脂可以预测疗法的生存和反应的假设，预计将减少 从肝细胞中释放电动汽车。第三，我们将开发并验证新的临床评估以诊断 啊。这是该多PI U01赠款应用程序将产生用于AH诊断和的液体活检生物标志物 预后。