SDR: Genomic analysis of blast tube induced TBI in mice

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ABSTRACT The neurological consequences of blast-induced traumatic brain injury (TBI) are a critical issue facing our Veterans. The effects of TBI-induced cognitive deficits can be devastating, yet little is known about the neuropathological progression initiated by potentially unique injury mechanisms caused by blast exposure. Indeed, TBI may initiate a continuum of neurodegenerative changes progressing for weeks, months, or even years following injury; however, the relationship between various genetic backgrounds and susceptibility or resilience to blast-induced neuropathological sequelae has not been established. The objective of the current proposal is to address this gap in knowledge, and is in response to the recent Request for Applications on “Genomic analysis of blast tube induced TBI in mice”. We propose to conduct a comparative study of the effect of and recovery from blast tube induced injury in eight strains of mice (A/J, C57Bl/6J, 129S1/SvlmJ, NOD/LtJ, NZO/HiLtJ, Ast/EiJ, PWK/PhJ and WSB/EiJ) that capture more than 90% of the genetic variation in commonly used laboratory mice. While the major objective is to establish relationships between underlying genetic profiles and neurobehavioral and neuropathological consequences of blast exposure, a detailed assessment of multi-organ pathology will also be performed. First, we will establish lethality exposure thresholds and the extent and nature of multi-organ pathology for each strain (Aim 1). Then we will use a multi-dimensional battery of behavioral testing to determine the extent of cognitive and motor deficits for each strain up to 1 month following blast exposure (Aim 2). Next, at discrete time points post-blast we will execute in-depth quantitative analyses of gene expression changes measuring hundreds of relevant genes and neuropathological sequelae using traditional immunohistochemistry as well as cutting-edge imaging mass spectrometry capable of quantifying levels of up to 37 proteins simultaneously (Aim 3). Finally, we will perform detailed statistical testing, including principal component analysis, to identify the relative contributions of various underlying genotypes on injury thresholds, organ pathology, behavioral deficits, gene expression, and neuropathology resulting from blast exposure. Of note, all data sets deriving from this study will be made available to the scientific community to provide a foundation for future analyses and formulation of data-driven hypotheses. The current proposed research will be executed through a long-standing collaboration between experts in conventional and blast-induced TBI spanning the Corporal Michael J. Crescenz (CMC) VA Medical Center and the University of Pennsylvania. Overall, the execution of this comprehensive study will identify genes that contribute to variations in susceptibility, resilience, and/or recovery from TBI, and thus will lay the foundation for future mechanism-based studies of therapeutic agents to blunt neurodegenerative sequelae and promote functional restoration following blast-TBI. As such, these studies will benefit the long-term health of our Veteran population as well as enrich the overall research program at the CMC VA Medical Center.