AMP-AD Brain Proteomic Network Enhancement, Validation, and Translation into CSF Biomarkers

AMP-AD 脑蛋白质组网络增强、验证并转化为 CSF 生物标志物

• 批准号: 10474124
• 负责人: ALLAN I LEVEY
• 金额: $ 1.36万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474124
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Alzheimer’s disease biomarker; Amyloid beta-Protein; Astrocytes; Autopsy; Biochemical; Bioinformatics; Biological Markers; Biological Models; Brain; Brain Pathology; Cerebrospinal Fluid; Clinical; Co-Immunoprecipitations; Cognition; Cognitive; Companions; Complement; Coupling; Cross-Sectional Studies; Data; Diagnosis; Dimensions; Disease; Drosophila genus; Environment; Experimental Models; Fractionation; Functional disorder; Future; Genetic; Goals; Human; Individual; Investigation; Knowledge; Label; Link; Mass Spectrum Analysis; Measures; Medicine; Methods; Microglia; Molecular; Monitor; Nerve Degeneration; Neuroglia; Neurons; Oligodendroglia; Pathology; Pathway interactions; Performance; Phase; Phosphorylation; Phosphorylation Site; Process; Proteins; Proteome; Proteomics; Reproducibility; Sampling; Set protein; Signal Transduction; Site; Structure; Synapses; Systems Biology; Technology; Testing; Therapeutic; Translating; Translations; Validation; age effect; base; biomarker panel; case control; cohort; collaborative approach; data sharing; diagnostic accuracy; disease classification; disorder control; improved; in vivo; innovation; metabolomics; mouse model; network architecture; neuropathology; new therapeutic target; next generation; novel; novel marker; phosphoproteomics; protein complex; protein protein interaction; response; targeted biomarker; tau Proteins; therapeutic target; tool; trait; transcriptomics; translational study; web interface

Project Summary There is an unmet need to develop novel therapeutic targets and biomarkers for Alzheimer's disease (AD) and related disorders. During the first phase of consortium, we have added the unique dimension of discovery proteomics to the Accelerating Medicines Partnership (AMP)-AD. We successfully established a high throughput proteomics pipeline and quantified 2-3000 proteins by mass spectrometry (MS) in >1800 postmortem human brains for all AMP-AD teams. Using systems biology tools, we identified highly conserved AD proteomic networks that complement and extend transcriptomic networks, highlighting a set of protein co-expression modules strongly associated with diagnosis, cognition, and neuropathology. Experimental validation of several novel protein targets in these modules confirmed links to neurodegeneration in model systems and in human brain pathology. The overall goal of this renewal application is to fill several key gaps in AMP-AD, which are to enrich and validate the AD brain co-expression network (with coverage of >11,000 proteins, >30,000 phosphosites, and interacting proteins), and better define optimal novel targets for the entire consortium. Using new MS technologies and proven cross-species experimental strategies, we will provide high confidence of module membership necessary to guide therapeutic and biomarker applications. We also will translate these targets into actionable biomarkers to monitor these modules and the respective pathophysiologies in living subjects with the following aims: 1) Integrate proteomics, phosphoproteomics and protein-protein interactions to extend AD networks and define key signaling and pathophysiological pathways linked to AMP-AD targets; 2) Validate predicted network structure for the most promising AMP-AD targets in experimental model systems; and 3) Translate the list of nominated AMP-AD targets including key trait-associated modules and hub proteins into novel CSF biomarkers for AD. The results will amplify the impact of the AMP-AD with rapid and full data sharing and establish an innovative pipeline for discovery and validation of brain proteomics targets and companion CSF biomarkers that serve as robust and reproducible indicators of AD, including the dysregulated processes that occur in brain.

项目摘要 存在开发用于阿尔茨海默病（AD）和阿尔茨海默病的新的治疗靶标和生物标志物的未满足的需求。 相关疾病。在联盟的第一阶段，我们增加了发现的独特维度 加速药物伙伴关系（AMP）-AD。我们成功地建立了一个高通量 蛋白质组学管道，并通过质谱（MS）在>1800个死后人体中定量2-3000种蛋白质 所有AMP-AD团队的大脑。利用系统生物学工具，我们鉴定了高度保守的AD蛋白质组网络 它补充和扩展了转录组学网络，突出了一组蛋白质共表达模块， 与诊断、认知和神经病理学密切相关。实验验证了几种新的 这些模块中的蛋白质靶点证实了模型系统和人脑中与神经退行性疾病的联系 病理此次更新申请的总体目标是填补AMP-AD中的几个关键空白， 并验证AD脑共表达网络（覆盖> 11，000种蛋白质，> 30，000个磷酸化位点， 相互作用的蛋白质），并更好地确定整个财团的最佳新目标。使用新MS 技术和经过验证的跨物种实验策略，我们将提供高信心的模块 指导治疗和生物标志物应用所需的成员资格。我们还将把这些目标转化为 可操作的生物标志物，以监测这些模块和患有这些疾病的活体受试者中的相应病理生理学。 目的：1）整合蛋白质组学、磷酸化蛋白质组学和蛋白质-蛋白质相互作用，扩展AD 网络，并定义与AMP-AD靶点相关的关键信号传导和病理生理学途径; 2） 实验模型系统中最有希望的AMP-AD靶标的预测网络结构;以及3） 将包括关键性状相关模块和中心蛋白在内的指定AMP-AD靶标列表翻译为 AD的新型CSF生物标志物。结果将通过快速和全面的数据共享扩大AMP-AD的影响 并建立一个创新的管道，用于发现和验证脑蛋白质组学靶点和伴随的CSF 生物标志物，作为AD的稳健和可重复的指标，包括失调的过程， 发生在大脑中。