A systems biology strategy to identify molecular mechanisms of action and protein indicators of traumatic brain injury.
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Date
2014-12-17
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Abstract
The multifactorial nature of traumatic brain injury TBI especially the complex secondary tissue injury involving intertwined networks of molecular pathways that mediate cellular behavior has confounded attempts to elucidate the pathology underlying the progression of TBI Here systems biology strategies are exploited to identify novel molecular mechanisms and protein indicators of brain injury To this end we performed a meta analysis of four distinct high throughput gene expression studies involving different animal models of TBI By using canonical pathways and a large human protein interaction network as a scaffold we separately overlaid the gene expression data from each study to identify molecular signatures that were conserved across the different studies At 24 hr after injury the significantly activated molecular signatures were nonspecific to TBI whereas the significantly suppressed molecular signatures were specific to the nervous system In particular we identified a suppressed subnetwork consisting of 58 highly interacting coregulated proteins associated with synaptic function We selected three proteins from this subnetwork postsynaptic density protein 95 nitric oxide synthase 1 and disrupted in schizophrenia 1 and hypothesized that their abundance would be significantly reduced after TBI In a penetrating ballistic like brain injury rat model of severe TBI Western blot analysis confirmed our hypothesis In addition our analysis recovered 12 previously identified protein biomarkers of TBI The results suggest that systems biology may provide an efficient high yield approach to generate testable hypotheses that can be experimentally validated to identify novel mechanisms of action and molecular indicators of TBI