A systems biology strategy to identify molecular mechanisms of action and protein indicators of traumatic brain injury.
Bottom Line: 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.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.
Affiliation: Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, Maryland.Show MeSH
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Mentions: We tested the hypothesized protein indicators at 24 hr after injury with a total of six rats separated into two groups, three subjected to 10% PBBI and three sham (controls), to determine whether abundance changes between the groups were suppressed as we had hypothesized. For both ipsilateral and contralateral tissues, we observed multiple immunoreactivity bands for DISC1 (Fig. 6A), corresponding to multiple DISC1 isoforms or their complex. Because of the indistinguishable neurological functions of these isoforms, their relative densities were compared as the aggregate of all detectable bands. Compared with sham, the abundance of DISC1 decreased by 47% in the ipsilateral tissues (P < 0.001 for between-group differences) but showed no significant differences in the contralateral tissues. We observed a significant decrease in the major isoform of PSD95 (95 kDa band) in ipsilateral PBBI tissues (69%, P < 0.05) and a nonsignificant increase (50%, P > 0.05) in the contralateral PBBI tissues (Fig. 6B). The protein's low-molecular-weight fragments (38 kDa and 25 kDa) were detectable only in the ipsilateral PBBI tissues. For NOS1, we observed an isoform of 160 kDa (α isoform) in both tissues for the two conditions, which showed a significant abundance decrease in the ipsilateral tissue (50%, P < 0.02) and the contralateral tissue (46%, P < 0.005). Another NOS1 isoform of 150 kDa (β isoform) was observed only in the ipsilateral PBBI tissues (Fig. 6C).
Affiliation: Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, Maryland.