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

项目摘要 开发阿尔茨海默病(AD)的新治疗靶点和生物标记物的需求尚未得到满足 相关的障碍。在财团的第一阶段，我们增加了发现的独特维度 蛋白质组学到加速药物伙伴关系(AMP)-AD。我们成功地建立了高吞吐量 蛋白质组学流水线和质谱学(MS)在1800人死后对2-3000个蛋白质的定量 适用于所有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 补充和扩展转录网络，突出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。几种小说的实验验证 这些模块中的蛋白质靶标证实了与模型系统和人脑中的神经退行性变有关 病理学。此续订申请的总体目标是填补AMP-AD中的几个关键空白，这些空白旨在丰富 并验证AD脑共表达网络(覆盖&gt；11,000个蛋白质，&gt；30,000个亚磷酸盐，以及 相互作用的蛋白质)，并更好地为整个财团定义最佳的新靶点。使用新的MS 技术和经过验证的跨物种实验策略，我们将提供高度自信的模块 指导治疗和生物标记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，用于监测这些模块和活体受试者的各自病理生理 目的如下：1)整合蛋白质组学、磷酸蛋白质组学和蛋白质-蛋白质相互作用以延长AD 网络并定义与AMP-AD靶点相关的关键信号和病理生理通路；2)验证 在实验模型系统中预测最有希望的AMP-AD目标的网络结构；以及3) 将包括关键特性相关模块和中枢蛋白在内的提名AMP-AD靶点列表翻译为 AD的新型脑脊液生物标志物。结果将通过快速和全面的数据共享放大AMP-AD的影响 并建立一个创新的渠道来发现和验证大脑蛋白质组学靶点和伴随的脑脊液 作为AD的可靠和可重复性指标的生物标志物，包括调节失调的过程 发生在大脑中。

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.