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.

抽象的 代谢组学是系统生物学的一个新兴领域，旨在全面分析多种代谢组学 生物样品中的代谢物由大量不同类别的化合物组成， 例如使用液体阐明氨基酸、脂质、有机酸和核苷酸的代谢变化。 色谱 (LC) 与质谱 (MS) 相结合增强了我们对早期通路的理解 与神经退行性变相关的扰动，并使得预测性生物标志物的开发成为可能 母公司 ABC-DS（阿尔茨海默氏症生物标志物联盟 - Downs）的总体目标 综合症）奖旨在明确唐氏综合症（DS）患者的阿尔茨海默病（AD）特征； 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体液特征和遗传测量的协调。 然而，针对 AD 病理学特有的基于血液的生物标志物的识别、验证和验证尚不明确。 受基体效应和大线性动态范围的限制，模糊了低电离和检测 丰富的化合物，否则可以成为临床前发病和进展的有力指标 DS 队列中的痴呆症。 我们正在申请资金购买 7500 QTrap® LC-MS/MS 系统（以下简称 7500 QTrap）， 扩展我们的定量 MS 迫切需要的新一代三重四极杆质谱仪 (MS) 我们最近的工作表明，代谢物属于 ABS-DS 联盟项目。 DS 和 AD 患者的能量代谢和 β-氧化途径显示出显着的失调。 请求的 7500 QTrap 将有助于加强生物标志物的发现、验证和确认工作流程 提议的生物标志物研究详见 ABC-DS 计划的项目 1、2 和 3。 将用于通过优先考虑 U19 样本来主要支持我们 NIA 资助的 U19 (1U19AG068054-01) 项目 当可用时，它可以用于其他项目相关的研究，例如我们的 NIA 资助的研究。 (R01AG058644) 项目结合了速度、鲁棒性、动态范围、 以及最大限度地减少交叉污染，这是成功定量分析所必需的 使用 LC-MS 分析代谢组样品。 7500 QTrap 将成为目标代谢组学工作流程的重大技术进步，因为 灵敏度（102 至 104）和分辨率的显着增强以及改进的分析流程 下游数据分析和处理结合起来，这将增强小分子的检测。 提高灵敏度并扩大母体生物流体生物标志物表征目标的范围 奖项，符合 FDA-MDDT 计划，用于开发具有转化价值的生物标志物。 该仪器将安装在乔治城大学的代谢组学核心设施中。