SDR: Genomic analysis of blast tube induced TBI in mice

摘要 爆炸引起的创伤性脑损伤（TBI）的神经学后果是我们面临的一个关键问题。 老兵TBI引起的认知缺陷的影响可能是毁灭性的，但人们对TBI引起的认知缺陷知之甚少。 由爆炸暴露引起的潜在独特损伤机制引发的神经病理学进展。 事实上，TBI可能引发持续数周、数月甚至数月的神经退行性变化， 然而，各种遗传背景和易感性之间的关系， 对爆炸引起的神经病理学后遗症的恢复能力尚未确定。当前的目标 建议是为了解决这一知识差距，并在回应最近的申请要求， "小鼠中爆炸管诱导的TBI的基因组分析"。我们建议进行一项比较研究， 在8个品系的小鼠（A/J，C57 B1/6J，129 S1/SvlmJ，NOD/LtJ， NZO/HiLtJ、Ast/EiJ、PWK/PhJ和WSB/EiJ），其通常捕获超过90%的遗传变异。 实验室老鼠虽然主要目标是建立潜在的遗传学之间的关系， 爆炸暴露的特征以及神经行为和神经病理学后果，详细评估 还将进行多器官病理学检查。首先，我们将确定致命性接触阈值， 每种菌株的多器官病理学的程度和性质（目的1）。然后我们将使用多维电池 行为测试，以确定每种应变的认知和运动缺陷的程度，长达1个月 爆炸后暴露（目标2）。接下来，在爆破后的离散时间点，我们将进行深入的定量分析， 分析基因表达变化，测量数百个相关基因和神经病理学后遗症 使用传统的免疫组织化学以及尖端的成像质谱， 同时定量多达37种蛋白质的水平（目标3）。最后，我们将详细统计 测试，包括主成分分析，以确定各种基础的相对贡献 基因型对损伤阈值、器官病理学、行为缺陷、基因表达和神经病理学的影响 是爆炸造成的值得注意的是，本研究得出的所有数据集将提供给 科学界的合作，为未来的分析和数据驱动的假设的制定提供基础。 目前拟议的研究将通过专家之间的长期合作来执行， 常规和爆炸引起的TBI跨越下士Michael J. Crescenz（CMC）VA医疗中心， 宾夕法尼亚大学总的来说，这项全面研究的执行将确定基因， 有助于TBI的易感性，弹性和/或恢复的变化，从而奠定基础 对于未来的机制为基础的研究治疗剂，以钝化神经退行性后遗症，并促进 爆炸性创伤后功能恢复因此，这些研究将有利于我们退伍军人的长期健康。 人口，以及丰富在CMC VA医疗中心的整体研究计划。

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.