Approximately 25% of the two million service personnel deployed since 2000 have reported receiving a traumatic brain injury (TBI). The vast majority of these are mild, and, in the military, due to exposure to blast waves from a variety of sources. Unfortunately, an effective treatment is still needed, meanwhile Veterans cope with long-term effects of impaired brain processing and neurodegeneration. A better understanding is needed to address the problems caused by TBI. Genetic predispositions to neuronal damage susceptibility versus predispositions to neuroprotective resilience and repair represent a understudied gap in our understanding of how to best treat the brain following a TBI. Moreover, as therapeutic approaches become more personalized, a robust understanding of the contributions of genetic background to TBI resilience and recovery is essential in order to develop solutions for our affected Veterans We will identify genes that affect the degree of blast-induced functional impairment and post-injury recovery by studying a set of model mouse strains that encompass most all of the genetic variations between laboratory strains. The injury model will utilize a well-established blast tube system designed to mimic pressure waves experienced during a field explosive detonation. A battery of behavioral tests will be performed at baseline prior to the injury and as long as 30 days after blast exposure to assess the role of genetics in recovery of functional outcomes, including different aspects of memory performance, anxiety, motor coordination, startle reactivity, and nesting. We will also compare TBI-induced region specific changes in markers of neurodegeneration and alterations in gene expression. We will also include examinations of other organs for blast-induced damage to see if the genetic factors influence the affects upon non-neuronal tissue. This research represents a multi-level examination of how certain genes influence blast-induced TBI and recovery. It will provide essential starting points for future investigations to understand how these genes play roles in the post-injury outcomes, to develop optimal models for blast studies, and to lead towards the definition of therapeutic targets that could be modulated to eventually improve the health of Veterans with histories of blast exposures.
Traumatic brain injury remains a prevalent problem among the Veteran population. Information about the influence of genetics has proven to be very useful for other disorders, however the genetic factors affecting the response to traumatic brain injury are largely unknown. We will take advantage of a set of model strains of mice that provide a high degree of genetic variation and examine the effects of blast-induced injury and the subsequent recovery. By comparing the course of behavioral deficits between the different strains, we will be able to determine the genes that are involved in the injury induced neurodegeneration and repair. The results of this project will provide a foundation for future work optimizing injury models and identifying therapeutic approaches that can be tailored to individuals based on genetic information.
