Ischemic stroke involves multiple pathophysiological mechanisms with complex interactions. Efforts to decipher those mechanisms and understand the evolution of cerebral injury is key for developing successful interventions. In an innovative approach, we use literature mining, natural language processing and systems biology tools to construct, annotate and curate a brain ischemia interactome. The curated interactome includes proteins that are deregulated after cerebral ischemia in human and experimental stroke. Network analysis of the interactome revealed a rich-club organization indicating the presence of a densely interconnected hub structure of prominent contributors to disease pathogenesis. Functional annotation of the interactome uncovered prominent pathways and highlighted the critical role of the complement and coagulation cascade in the initiation and amplification of injury starting by activation of the rich-club. We performed an in-silico screen for putative interventions that have pleiotropic effects on rich-club components and we identified estrogen as a prominent candidate. Our findings show that complex network analysis of disease related interactomes may lead to a better understanding of pathogenic mechanisms and provide cost-effective and mechanism-based discovery of candidate therapeutics.

Spinal cord injury (SCI) is associated with complex pathophysiological processes that follow the primary traumatic event and determine the extent of secondary damage and functional recovery. Numerous reports have used global and hypothesis-driven approaches to identify protein changes that contribute to the overall pathology of SCI in an effort to identify potential therapeutic interventions. In this study, we use a semi-automatic annotation approach to detect terms referring to genes or proteins dysregulated in the SCI literature and develop a curated SCI interactome. Network analysis of the SCI interactome revealed the presence of a rich-club organization corresponding to a “powerhouse” of highly interacting hub-proteins. Studying the modular organization of the network have shown that rich-club proteins cluster into modules that are specifically enriched for biological processes that fall under the categories of cell death, inflammation, injury recognition and systems development. Pathway analysis of the interactome and the rich-club revealed high similarity indicating the role of the rich-club proteins as hubs of the most prominent pathways in disease pathophysiology and illustrating the centrality of pro-and anti-survival signal competition in the pathology of SCI. In addition, evaluation of centrality measures of single nodes within the rich-club have revealed that neuronal growth factor (NGF), caspase 3, and H-Ras are the most central nodes and potentially an interesting targets for therapy. Our integrative approach uncovers the molecular architecture of SCI interactome, and provide an essential resource for evaluating significant therapeutic candidates.