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

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ABSTRACT for parent currently funded U01 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.