title: Military personnel with chronic symptoms following blast traumatic brain injury have differential expression of neuronal recovery and epidermal growth factor receptor genes.
abstract: OBJECTIVE
  Approximately one-quarter of military personnel who deployed to combat stations sustained one or more blast-related, closed-head injuries. Blast injuries result from the detonation of an explosive device. The mechanisms associated with blast exposure that give rise to traumatic brain injury (TBI), and place military personnel at high risk for chronic symptoms of post-concussive disorder (PCD), post-traumatic stress disorder (PTSD), and depression are not elucidated.
  
  
  METHODS
  To investigate the mechanisms of persistent blast-related symptoms, we examined expression profiles of transcripts across the genome to determine the role of gene activity in chronic symptoms following blast-TBI. Active duty military personnel with (1) a medical record of a blast-TBI that occurred during deployment (n = 19) were compared to control participants without TBI (n = 17). Controls were matched to cases on demographic factors including age, gender, and race, and also in diagnoses of sleep disturbance, and symptoms of PTSD and depression. Due to the high number of PCD symptoms in the TBI+ group, we did not match on this variable. Using expression profiles of transcripts in microarray platform in peripheral samples of whole blood, significantly differentially expressed gene lists were generated. Statistical threshold is based on criteria of 1.5 magnitude fold-change (up or down) and p-values with multiple test correction (false discovery rate <0.05).
  
  
  RESULTS
  There were 34 transcripts in 29 genes that were differentially regulated in blast-TBI participants compared to controls. Up-regulated genes included epithelial cell transforming sequence and zinc finger proteins, which are necessary for astrocyte differentiation following injury. Tensin-1, which has been implicated in neuronal recovery in pre-clinical TBI models, was down-regulated in blast-TBI participants. Protein ubiquitination genes, such as epidermal growth factor receptor, were also down-regulated and identified as the central regulators in the gene network determined by interaction pathway analysis.
  
  
  CONCLUSIONS
  In this study, we identified a gene-expression pathway of delayed neuronal recovery in military personnel a blast-TBI and chronic symptoms. Future work is needed to determine if therapeutic agents that regulate these pathways may provide novel treatments for chronic blast-TBI-related symptoms.
authors.affiliation: National Institute of Nursing Research, National Institutes of Health , Bethesda, MD , USA.
authors.forename: Morgan
authors.initials: M
authors.lastname: Heinzelmann
authors.affiliation: National Institute of Nursing Research, National Institutes of Health , Bethesda, MD , USA.
authors.forename: Swarnalatha Y
authors.initials: SY
authors.lastname: Reddy
authors.affiliation: Center for Neuroscience and Regenerative Medicine , Bethesda, MD , USA ; Defense and Veterans Brain Injury Center, Walter Reed National Military Medical Center , Bethesda, MD , USA.
authors.forename: Louis M
authors.initials: LM
authors.lastname: French
authors.affiliation: National Institute of Nursing Research, National Institutes of Health , Bethesda, MD , USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.affiliation: National Institute of Nursing Research, National Institutes of Health , Bethesda, MD , USA.
authors.forename: Hyunhwa
authors.initials: H
authors.lastname: Lee
authors.affiliation: West Virginia University Health Sciences Center , Morgantown, WV , USA.
authors.forename: Taura
authors.initials: T
authors.lastname: Barr
authors.affiliation: Sleep Medicine Clinic, Madigan Army Medical Center , Tacoma, WA , USA.
authors.forename: Tristin
authors.initials: T
authors.lastname: Baxter
authors.affiliation: Sleep Medicine Clinic, Madigan Army Medical Center , Tacoma, WA , USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Mysliwiec
authors.affiliation: National Institute of Nursing Research, National Institutes of Health , Bethesda, MD , USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Gill
keywords: gene-expression; military; post-concussive disorder; traumatic brain injury