A systems biology strategy to identify molecular mechanisms of action and protein indicators of traumatic brain injury.
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.
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.
Chenggang
C
Yu
Angela
A
Boutté
Xueping
X
Yu
Bhaskar
B
Dutta
Jacob D
JD
Feala
Kara
K
Schmid
Jitendra
J
Dave
Gregory J
GJ
Tawa
Anders
A
Wallqvist
Jaques
J
Reifman
D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D001930:Brain Injuries / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D005786:Gene Expression Regulation / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D049490:Systems Biology / Q000379:methods*
D015415:Biomarkers; C498795:Disc1 protein, rat; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D052248:Nitric Oxide Synthase Type I
biomarkers; pathway analysis; protein-protein interaction networks; systems biology; traumatic brain injury