Multi-omic network-directed proteoform discovery, dissection and functional validation to prioritize novel AD therapeutic targets

在加速阿尔茨海默病药物伙伴关系（AMP-AD）的第一阶段，我们 完成了从分子网络构建和确认开始的新型靶点验证弧， 进展到识别网络中的驱动基因，并以目标基因验证结束，通过两个 体外扰动和靶器官中的蛋白质组学测量。在这里，我们描述那些验证 并部署了第三代网络图，其中包含来自单细胞的数据 从500个大脑中提取，以产生我们网络的细胞类型特定版本。此外，在发现 阶段，我们将使用蛋白质翻译后修饰的评估，以确定通常 迄今为止，组织水平的大脑RNA和通用蛋白质水平掩盖了这一点。新 网络还将整合最新的AMP-AD数据，涵盖基因组学，转录组学，表观基因组学，蛋白质组学， 以及来自不同成员群体的代谢组学数据集。由此产生的新目标，沿着 在第一个资助周期中得到验证的蛋白质，将进行进一步的解剖，以了解哪种蛋白质亚型或 修饰与疾病最相关。我们继续进行微扰实验的每一个 在富集的体外多细胞培养环境中优先考虑基因，并鉴定关键蛋白质结构域 在选定的候选人中。最后，我们扩大我们的研究资源共享中心，促进 从我们的项目的样本和数据的分布。

In the first period of the Accelerating Medicines Partnership for Alzheimer’s Disease (AMP-AD), we completed an arc of novel target validation that began with molecular network construction and confirmation, progressed to identifying driver genes within the network, and ended with target gene validation, through both in vitro perturbation and proteomic measurement in the target organ. Here, we characterize those validated genes in greater detail and deploy a third-generation network map that incorporates data from single cells extracted from 500 brains to produce a cell-type specific version of our networks. Further, in the discovery phase, we will use an assessment of protein post-translational modifications to identify targets that are typically masked in the tissue-level brain RNA and generic protein levels that have been available to date. The new network will also integrate the latest AMP-AD data, spanning genomic, transcriptomic, epigenomic, proteomic, and metabolomic data sets from the various member groups. The resulting new targets, along with those validated in the first funding cycle, will undergo further dissection to understand which protein isoform or modification is most relevant to disease. We go on to perform perturbation experiments for each of the prioritized genes in an enriched in vitro multicellular culture context and to identify critical protein domains within selected candidates. Finally, we expand our Research Resource Sharing Hub that facilitates the distribution of samples and data from our project.