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，其目的是综合分析各种 生物样品中的代谢物。代谢组由大量不同类别的化合物组成， 如氨基酸、脂类、有机酸和核苷酸。用液体阐明代谢变化 层析(LC)和质谱学(MS)的结合增加了我们对早期途径的了解 与神经退行性变相关的扰动，并使预测生物标志物的发展成为可能。 临床痴呆症。父母ABC-DS(阿尔茨海默病生物标记物联合会-Down)的首要目标 综合征)奖是为了描述唐氏综合症(DS)患者的阿尔茨海默病(AD)的特征；具体来说 项目2和3旨在将成果转化为精确医学框架，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特征和遗传措施的协调。 然而，识别、验证和确认AD病理的血液生物标记物是 受基质效应和大的线性动态范围的限制，其模糊了低电离和检测 丰富的化合物，否则可能是临床前疾病发生和发展的有力指标 DS队列中的痴呆症。 我们正在请求资金购买7500 QTrap®LC-MS/MS系统(此后为7500 QTrap)，Next 扩展我国定量质谱仪急需的新一代三重四极质谱计 ABS-DS财团项目的能力。我们最近的研究表明，属于 在DS和AD患者中，能量代谢和β-氧化途径显示出明显的失调。这个 申请7500 QTrap将有助于加强生物标记物发现、验证和验证工作流程 ABC-DS计划的项目1、2和3中详细介绍了拟议的生物标记物研究。这项设备补充 将主要用于支持我们由NIA资助的U19(1U19AG068054-01)项目，方法是优先选择U19样本 以供分析。当它可用时，它可以用于其他项目相关研究，例如我们的NIA资助的 (R01AG058644)项目。该系统结合了速度、健壮性、动态范围、 以及最大限度地减少交叉污染，这是成功定量询问所必需的 代谢物样品的LC-MS分析 7500 QTrap将是靶向代谢组学工作流程的重大技术进步，因为 显著提高了灵敏度(102至104)和分辨率，并改进了分析管道 下游数据的分析和处理。总而言之，这将增强对小分子的探测 具有更高的灵敏度，并扩大了生物流体生物标记物的亲本表征目标范围 根据FDA-MDDT计划，开发具有翻译价值的生物标记物。这 仪器将安装在乔治敦大学的代谢组学核心设施中。