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: 10013105
• 负责人: ALLAN I LEVEY
• 金额: $ 186.12万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10013105
• 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 有未满足的需要开发新颖的治疗靶标和生物标志物来为阿尔茨海默氏病（AD）和 相关疾病。在财团的第一阶段，我们添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 蛋白质组学管道和通过质谱法（MS）量化的2-3000蛋白质> 1800后人类 所有AMP-AD团队的大脑。使用系统生物学工具，我们确定了高度保守的AD蛋白质组学网络 该补充并扩展了转录组网络，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。几种新颖的实验验证 这些模块中的蛋白质靶标证实了与模型系统和人脑中神经退行性的联系 病理。此更新申请的总体目标是填补AMP-AD中的几个关键空白，这些空白是为了丰富 并验证广告大脑共表达网络（覆盖范围> 11,000蛋白，> 30,000磷脂和 相互作用的蛋白质），并更好地定义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，我们将提供模块的高信心 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与生物生物生物生物生物生物生物学 以下目的：1）整合蛋白质组学，磷酸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目标相关的关键信号传导和病理生理途径； 2）验证 实验模型系统中最有希望的AMP-AD目标的预测网络结构； 3） 将包括密钥性状相关模块和集线器蛋白在内的提名AMP-AD目标列表转换为 AD的新型CSF生物标志物。结果将通过快速和完整的数据共享扩大AMP-AD的影响 并建立创新的管道，以发现和验证脑蛋白质组学目标和伴侣CSF 作为AD的强大和可重复指标的生物标志物，包括失调的过程 发生在大脑中。