Metabolomics-based discovery of small molecule biomarkers for noninvasive dengue

基于代谢组学的非侵入性登革热小分子生物标志物的发现

• 批准号: 8841436
• 负责人: Rushika Perera
• 金额: $ 40.29万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8841436
• 关键词: Acute; Affect; Algorithms; Bedside Testings; Biological; Biological Markers; Blood specimen; California; Cell physiology; Cells; Cessation of life; Childhood; Clinical; Clinical Course of Disease; Clinical Data; Clinical Research; Clinics and Hospitals; Cohort Studies; Colorado; Communities; Computer software; Country; Databases; Dengue; Dengue Hemorrhagic Fever; Dengue Virus; Detection; Development; Devices; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease Outcome; Environment; Epidemic; Fingerprint; Funding Mechanisms; Generations; Goals; Health; Hemorrhagic Shock; Hospitals; Immunoglobulin M; Individual; Industry; Infection; Laboratories; Latin America; Liquid Chromatography; Liquid substance; Machine Learning; Mass Spectrum Analysis; Metabolic; Metabolic Pathway; Metabolism; Mexico; Molecular; Molecular Weight; Multivariate Analysis; Nicaragua; Nicaraguan; Patient Care; Patient Care Management; Patient Triage; Patients; Phase; Physicians; Physiological; Prognostic Marker; Public Health; Qualifying; Regimen; Reporting; Research; Risk; Saliva; Sampling; Scientist; Sensitivity and Specificity; Serum; Shock; Signs and Symptoms; Specimen; Supportive care; Syndrome; System; Testing; Therapeutic Intervention; Tissues; Universities; Urine; Virus Diseases; base; clinical care; disease diagnosis; innovation; liquid chromatography mass spectrometry; metabolomics; outcome forecast; point-of-care diagnostics; prognostic; programs; prospective; small molecule; tandem mass spectrometry

PROJECT SUMMARY / ABSTRACT Epidemic dengue fever (DF) and dengue hemorrhagic fever (DHF/DSS) have emerged throughout the tropical world with devastating public health consequences. A dramatic increase in severe dengue disease (DEN) in Latin America in the last decade is of grave concern; 30% of cases are now diagnosed as severe dengue virus (DENV) infections. DEN is overwhelming public health capacity for clinical care in much of the developing world. The overall goal of this proposal is to provide a major change in the diagnosis and prognosis (D&P) of DENV infections. A metabolomics approach will be used to identify candidate metabolite small molecule biomarkers (SMBs) that occur both in serum and in non-invasive clinical specimens (urine and saliva) that diagnose DENV infection and predict progression to severe disease. Preliminary studies using acute phase specimens from DEN patients have identified a number of molecular features and candidate SMBs of DF and DHF/SS in serum, saliva, and urine using liquid chromatography-mass spectrometry (LC-MS)-based metabolomics. In the R21 phase of this project, we will use a metabolic fingerprinting approach to confim existing and identify new candidate SMBs in retrospectively collected serum specimens available from the high-quality pediatric DEN hospital-based and cohort studies in Nicaragua, will begin to characterize the SMBs and metabolic pathways involved, will investigate the efficacy for D&P of these SMBs in prospectively collected serum, saliva, and urine specimens in the hospital study, and will identify a portfolio of the most significant molecular features that differentiate DEN, severe DEN, and non-DEN disease. We will develop algorithms including SMBs, clinical signs and symptoms, and clinical laboratory results for the D&P of DENV infections. In the R33 phase of the project, prospectively collected serum, saliva, and urine samples from both the hospital study and a community-based cohort study will be analyzed by metabolic profiling using LC-tandem MS (LC- MS/MS) to identify candidate SMBs. First generation EIA tests for selected SMBs will be included in the diagnostic regimen in Nicaragua The diagnostic and prognostic sensitivity and specificity of the candidate SMBs and "first generation" SMB tests will be determined as will the preferred clinical specimen for SMB- based diagnoses. Overall these studies will identify a panel of SMBs (e.g., 5-10), which will be used to formulate the Target Product Profiles (TPP) for rapid point-of-care (POC) tests for use in clinics and hospitals for DEN D&P. Detection of SMBs in saliva and urine that are predictive of severe DEN is innovative and provides the opportunity for a true paradigm shift in diagnosis by using inexpensive, easily procured, non- invasive clinical specimens for D&P of DEN.

项目摘要 /摘要 流行病登革热（DF）和登革热出血热（DHF/DSS）在整个热带中都出现 世界带来毁灭性的公共卫生后果。严重登革热疾病（DEN）的急剧增加 在过去的十年中，拉丁美洲令人担忧。现在有30％的病例被诊断为严重的登革热 病毒（DENV）感染。 DEN在大多数发展中的公共卫生能力压倒性的公共卫生能力 世界。该提案的总体目标是提供诊断和预后（D＆P）的重大变化 DENV感染。代谢组学方法将用于识别候选代谢物小分子 在血清和非侵入性临床标本（尿液和唾液）中发生的生物标志物（SMB） 诊断DENV感染并预测到严重疾病的进展。使用急性期的初步研究 来自DEN患者的标本已经确定了许多分子特征和DF的候选中小型企业 基于液相色谱 - 质谱法（LC-MS）的DHF/SS血清，唾液和尿液中的DHF/SS 代谢组学。在该项目的R21阶段，我们将使用代谢指纹方法来束缚 现有并在回顾性收集的血清标本中确定新的候选中小企业 尼加拉瓜的高质量小儿丹医院和队列研究将开始表征中小型企业 涉及的代谢途径将研究这些中小型企业的D＆P的功效 医院研究中的血清，唾液和尿液标本，将确定最重要的投资组合 分子特征，可以区分DEN，严重的DEN和非疾病。我们将开发算法 包括SMB，临床体征和症状以及DENV感染D＆P的临床实验室结果。在 该项目的R33阶段，来自医院的前瞻性收集血清，唾液和尿液样本 研究和基于社区的队列研究将通过使用LC-Tandem MS（LC-）代谢分析来分析 MS/MS）以识别候选中小型企业。选定SMB的第一代EIA测试将包括 尼加拉瓜的诊断方案诊断和预后敏感性和特异性 SMB和“第一代” SMB测试将被确定，而SMB的首选临床标本也将确定 基于诊断。总体而言，这些研究将确定一组中小型企业（例如5-10），该小组将用于 制定目标产品概况（TPP），以进行快速护理（POC）测试，用于诊所和医院 对于Den D＆P。检测唾液和尿液中预测严重DEN的中小型企业是创新的，并且 通过使用廉价，易于购买的，非 - DEN D＆P的侵入性临床标本。