Abstract
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.
Highlights
Network analysis tools were previously used to analyze biological networks including protein-protein interaction networks and neuronal connectivity networks[7,8,9]
A total of 8,740 papers were selected through the initial screening and gene products reported in these studies are included in the Brain Ischemia Interactome (BII)
The main findings of this study are the detection of a rich-club organization within the brain ischemia protein interaction network and the use of network analysis to identify prominent interacting pathways in disease pathophysiology
Summary
Network analysis tools were previously used to analyze biological networks including protein-protein interaction networks and neuronal connectivity networks[7,8,9]. We curated and annotated a brain-ischemia interactome (BII) referring to set of interactions among proteins reported to exhibit changes in levels or regulation after human or experimental stroke. Drug-protein interaction networks were used as an in-silico screening tool for putative therapeutic interventions that target the stroke rich-club.
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