title: Bilateral gene interaction hierarchy analysis of the cell death gene response emphasizes the significance of cell cycle genes following unilateral traumatic brain injury.
abstract: BACKGROUND
  Delayed or secondary cell death that is caused by a cascade of cellular and molecular processes initiated by traumatic brain injury (TBI) may be reduced or prevented if an effective neuroprotective strategy is employed. Microarray and subsequent bioinformatic analyses were used to determine which genes, pathways and networks were significantly altered 24 h after unilateral TBI in the rat. Ipsilateral hemi-brain, the corresponding contralateral hemi-brain, and naïve (control) brain tissue were used for microarray analysis.
  
  
  RESULTS
  Ingenuity Pathway Analysis showed cell death and survival (CD) to be a top molecular and cellular function associated with TBI on both sides of the brain. One major finding was that the overall gene expression pattern suggested an increase in CD genes in ipsilateral brain tissue and suppression of CD genes contralateral to the injury which may indicate an endogenous protective mechanism. We created networks of genes of interest (GOI) and ranked the genes by the number of direct connections each had in the GOI networks, creating gene interaction hierarchies (GIHs). Cell cycle was determined from the resultant GIHs to be a significant molecular and cellular function in post-TBI CD gene response.
  
  
  CONCLUSIONS
  Cell cycle and apoptosis signalling genes that were highly ranked in the GIHs and exhibited either the inverse ipsilateral/contralateral expression pattern or contralateral suppression were identified and included STAT3, CCND1, CCND2, and BAX. Additional exploration into the remote suppression of CD genes may provide insight into neuroprotective mechanisms that could be used to develop therapies to prevent cell death following TBI.
authors.affiliation: Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA, 30310, USA. twhite@msm.edu.
authors.forename: Todd E
authors.initials: TE
authors.lastname: White
authors.affiliation: Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA, 30310, USA. msurles@msm.edu.
authors.forename: Monique C
authors.initials: MC
authors.lastname: Surles-Zeigler
authors.affiliation: Division of Natural Sciences and Physical Education, Georgia Highlands College, 5441 Highway 20, NE, Cartersville, GA, 30121, USA. gford@highlands.edu.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Ford
authors.affiliation: Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA, 30310, USA. arenee277@yahoo.com.
authors.forename: Alicia S
authors.initials: AS
authors.lastname: Gates
authors.affiliation: Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA, 30310, USA. benemdavids@gmail.com.
authors.forename: Benem
authors.initials: B
authors.lastname: Davids
authors.affiliation: Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA, 30310, USA. timothy.distel@medsch.ucr.edu.|University of California-Riverside School of Medicine, 900 University Ave., Riverside, CA, 92521, USA. timothy.distel@medsch.ucr.edu.
authors.forename: Timothy
authors.initials: T
authors.lastname: Distel
authors.affiliation: Department of Biomedical Engineering, Georgia Institute of Technology, 313 Ferst Drive, Atlanta, GA, 30332, USA. laplaca@gatech.edu.
authors.forename: Michelle C
authors.initials: MC
authors.lastname: LaPlaca
authors.affiliation: Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA, 30310, USA. byron.ford@ucr.edu.|University of California-Riverside School of Medicine, 900 University Ave., Riverside, CA, 92521, USA. byron.ford@ucr.edu.
authors.forename: Byron D
authors.initials: BD
authors.lastname: Ford
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000503:physiopathology; D001930:Brain Injuries / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics*; D016923:Cell Death / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics; D056742:Cyclin D2 / Q000235:genetics; D004843:Epistasis, Genetic; D053263:Gene Regulatory Networks; D008297:Male; D046228:Microarray Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: C494828:Bax protein, rat; C530106:Ccnd1 protein, rat; C486197:Ccnd2 protein, rat; D056742:Cyclin D2; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D051028:bcl-2-Associated X Protein; D019938:Cyclin D1