Alzheimer Biomarker Consortium - Down Syndrome (ABC-DS)

阿尔茨海默病生物标志物联盟 - 唐氏综合症 (ABC-DS)

• 批准号: 10454470
• 负责人: BENJAMIN L HANDEN
• 金额: $ 25万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454470
• 关键词: Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amino Acids; Area; Award; Biological; Biological Markers; Biology; Clinical; Clinical Trials; Core Facility; Coupled; Data Analyses; Dementia; Detection; Development; Down Syndrome; Energy Metabolism; Equipment; Funding; General Population; Genetic; Goals; Health Promotion; Intervention; Lipids; Liquid Chromatography; Mass Spectrum Analysis; Measures; Metabolic; Nerve Degeneration; Neuropsychology; Nucleotides; Outcome; Parents; Pathway interactions; Public Health; Resolution; Sampling; Speed; System; Systems Biology; Translating; Universities; Work; aging population; biomarker discovery; blood-based biomarker; cohort; computerized data processing; high risk; improved; instrument; ionization; liquid chromatography mass spectrometry; mass spectrometer; metabolome; metabolomics; next generation; organic acid; oxidation; pre-clinical; precision medicine; predictive marker; programs; small molecule; specific biomarkers; verification and validation

Abstract Metabolomics is an emerging area of systems biology which aims to comprehensively analyze a wide array of metabolites in biological samples. The metabolome consists of a vast number of different classes of compounds, such as amino acids, lipids, organic acids and nucleotides. Elucidation of metabolic alterations using liquid chromatography (LC) coupled with mass spectrometry (MS) has increased our understanding of early pathway perturbations associated with neurodegeneration and enabled the development of predictive biomarkers of pre- clinical dementia. The overarching goal of the parent ABC-DS (Alzheimer’s Biomarkers Consortium - Downs Syndrome) award is to characterize Alzheimer’s disease (AD) in people with Down syndrome (DS); specifically projects 2 and 3 aim to translate outcomes to a precision medicine framework and expedite clinical trials via harmonization of clinical and neuropsychological outcomes with biofluid characterization and genetic measures. However, identification, verification and validation of blood based biomarkers specific to AD pathology is constrained by matrix effects and a large linear dynamic range that obscures the ionization and detection of low abundance compounds that could otherwise be powerful indicators of onset and progression of pre-clinical dementia in the DS cohort. We are requesting funds for the purchase of the 7500 QTrap® LC-MS/MS system (7500 QTrap hereafter), a next generation triple quadrupole mass spectrometer (MS) that is urgently needed for expanding our quantitative MS capabilities for the ABS-DS consortium projects. Our recent work has shown that metabolites belonging to energy metabolism and beta-oxidation pathways show significant dysregulation in people with DS and AD. The requested 7500 QTrap will help to strengthen biomarker discovery, verification and validation workflows for proposed biomarker studies detailed in Projects 1, 2 and 3 of the ABC-DS program. This equipment supplement will be used to primarily support our NIA-funded U19 (1U19AG068054-01) project by prioritizing U19 samples for analysis. When available, it may be used in other program related studies, such as our NIA-funded (R01AG058644) project. This system combines the requisite attributes of speed, robustness, dynamic range, and minimization of cross-contamination that is necessary for successful quantitative interrogation of metabolomic samples using LC-MS. The 7500 QTrap will be a significant technological advancement for targeted metabolomics workflows due to dramatic enhancements in sensitivity (102 to 104) and resolution as well as improved analytical pipelines for downstream data analysis and processing. Taken together, this would augment the detection of small molecules with improved sensitivity and expand the scope of biofluid biomarker characterization objectives of the parent award, in compliance with the FDA-MDDT program for developing biomarkers with translational value. This instrument will be housed at the metabolomics core facility in Georgetown University.

摘要 代谢组学是系统生物学的一个新兴领域，其目的是全面分析各种代谢产物， 生物样品中的代谢物。代谢组由大量不同种类的化合物组成， 例如氨基酸、脂质、有机酸和核苷酸。使用液体阐明代谢改变 色谱（LC）与质谱（MS）联用增加了我们对早期途径的理解， 与神经退行性变相关的扰动，并使发展的预测生物标志物， 临床痴呆母公司ABC-DS（阿尔茨海默氏症生物标志物联盟-唐斯）的首要目标是 综合征）奖是为了表征阿尔茨海默病（AD）的人与唐氏综合征（DS）;具体 项目2和3旨在将成果转化为精准医学框架，并通过以下方式加快临床试验： 临床和神经心理学结果与生物流体表征和遗传测量的协调。 然而，对AD病理学特异性的基于血液的生物标志物的鉴定、验证和确认是困难的。 受到基质效应和大的线性动态范围的限制，这使得低浓度的电离和检测变得模糊不清。 丰富的化合物，否则可能是发病和临床前进展的有力指标， DS队列中的痴呆症。 我们正在申请购买7500 QTrap® LC-MS/MS系统（以下简称7500 QTrap）的资金， 三重四极杆质谱仪（MS），迫切需要扩大我们的定量MS ABS-DS联盟项目的能力。我们最近的工作表明，属于 能量代谢和β-氧化途径在DS和AD患者中显示出显著的失调。的 要求的7500 QTrap将有助于加强生物标志物发现，验证和确认工作流程， 在ABC-DS计划的项目1、2和3中详细描述了拟议的生物标志物研究。该设备补充 将通过优先处理U19样本，主要用于支持我们的NIA资助的U19（1U 19 AG 068054 -01）项目 用于分析当可用时，它可以用于其他计划相关的研究，例如我们的NIA资助的 （R 01 AG 058644）项目。该系统结合了速度、鲁棒性、动态范围 和最小化交叉污染，这是成功定量询问所必需的， 使用LC-MS分析代谢组学样品。 7500 QTrap将是靶向代谢组学工作流程的重大技术进步， 灵敏度（102至104）和分辨率的显著提高以及分析管道的改进， 下游数据分析和处理。总之，这将增强对小分子的检测 具有提高的灵敏度和扩大生物流体生物标志物表征范围的目的 该奖项符合FDA-MDDT开发具有转化价值的生物标志物的计划。这 仪器将被安置在乔治敦大学的代谢组学核心设施。