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: 10475094
• 负责人: ALLAN I LEVEY
• 金额: $ 156.12万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10475094
• 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.

项目概要 开发阿尔茨海默病 (AD) 和生物标志物的新治疗靶点和生物标志物的需求尚未得到满足 相关疾病。在联盟的第一阶段，我们增加了发现的独特维度 加速药物合作伙伴关系 (AMP)-AD 的蛋白质组学。我们成功建立了高吞吐量 蛋白质组学流程，通过质谱 (MS) 对超过 1800 名死后人类的 2-3000 种蛋白质进行定量 所有 AMP-AD 团队的大脑。使用系统生物学工具，我们鉴定了高度保守的 AD 蛋白质组网络 补充和扩展转录组网络，突出显示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。几种新颖的实验验证 这些模块中的蛋白质靶点证实了模型系统和人脑中神经退行性变的联系 病理。此更新应用程序的总体目标是填补 AMP-AD 中的几个关键空白，即丰富 并验证 AD 大脑共表达网络（覆盖 >11,000 个蛋白质、>30,000 个磷酸位点，以及 相互作用的蛋白质），并更好地为整个联盟定义最佳的新靶点。使用新的 MS 技术和经过验证的跨物种实验策略，我们将为模块提供高信心 指导治疗和生物标志物应用所需的会员资格。我们还将把这些目标转化为 可操作的生物标志物来监测这些模块以及活体受试者各自的病理生理学 以下目标：1) 整合蛋白质组学、磷酸化蛋白质组学和蛋白质-蛋白质相互作用以扩展 AD 网络并定义与 AMP-AD 靶标相关的关键信号传导和病理生理学途径； 2）验证 预测实验模型系统中最有前途的 AMP-AD 目标的网络结构；和 3) 将提名的 AMP-AD 靶标列表（包括关键性状相关模块和枢纽蛋白）转化为 AD 的新型 CSF 生物标志物。结果将通过快速、全面的数据共享来放大 AMP-AD 的影响 并建立一个创新的管道来发现和验证脑蛋白质组目标和配套的 CSF 作为 AD 稳健且可重复指标的生物标志物，包括失调的过程 发生在大脑中。