SDR: Genomic analysis of blast tube induced TBI in mice

SDR：小鼠爆管诱发 TBI 的基因组分析

• 批准号: 9916439
• 负责人: Daniel Kacy Cullen
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916439
• 关键词: Address; Anatomy; Animals; Behavioral; Biomedical Engineering; Cognitive deficits; Collaborations; Communities; Comparative Study; Data; Data Set; Doctor of Philosophy; Doctor of Veterinary Medicine; Equilibrium; Exposure to; Formulation; Foundations; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Variation; Genomics; Genotype; Health; Heart; Image; Immunohistochemistry; Incidence; Injury; Intestines; Kidney; Knowledge; Laboratory mice; Learning; Lung; Mass Spectrum Analysis; Measures; Medical center; Memory; Motor; Mouse Strains; Mus; Nature; Nerve Degeneration; Neurologic; Organ; Pathologic; Pathologist; Pathology; Pennsylvania; Population; Predisposition; Principal Component Analysis; Proteins; Recording of previous events; Recovery; Request for Applications; Research; Research Personnel; Spleen; Statistical Models; Technology; Testing; Therapeutic Agents; Therapeutic Studies; Time; Traumatic Brain Injury; Traumatic Brain Injury recovery; Tube; Universities; Variant; Veterans; Veterinary Medicine; Veterinary Schools; War; Work; base; behavior test; body system; discrete time; functional restoration; genetic profiling; improved; morris water maze; mortality; motor deficit; neurobehavioral; neuropathology; neurosurgery; novel; object recognition; preclinical study; programs; quantitative imaging; resilience; response; transcriptome; transcriptome sequencing

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.

抽象的 爆炸引起的创伤性脑损伤（TBI）的神经系统后果是我们面临的关键问题 退伍军人。 TBI引起的认知缺陷的影响可能是毁灭性的，但对此知之甚少 神经病理学进展是由爆炸暴露引起的潜在独特损伤机制引发的。 实际上，TBI可能会启动一系列神经退行性变化的连续性，几周，几个月甚至 受伤后的几年；但是，各种遗传背景与敏感性之间的关系或 尚未确定对爆炸引起的神经病理后遗症的弹性。电流的目的 建议是在知识上解决这一差距，并回应最近对申请的要求 “爆炸管诱导小鼠TBI的基因组分析”。我们建议对效果进行比较研究 八只小鼠菌株中爆炸管诱导的损伤的恢复（A/J，C57BL/6J，129S1/SVLMJ，nod/ltj， NZO/HILTJ，AST/EIJ，PWK/PHJ和WSB/EIJ）捕获了通常的90％以上的遗传变异 二手实验室小鼠。虽然主要目标是建立基本遗传的关系 爆炸暴露的概况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。首先，我们将建立致死性暴露阈值和 每种菌株的多器官病理的范围和性质（AIM 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程度和电动机的程度最多1个月 爆炸暴露后（AIM 2）。接下来，在Blast后离散时间点我们将执行深入的定量 基因表达变化的分析，测量了数百种相关基因和神经病理后遗症 使用传统的免疫组织化学以及尖端的成像质谱法 简单地量化37种蛋白质的水平（AIM 3）。最后，我们将执行详细的统计数据 测试，包括主要成分分析，以确定各种基础的相对贡献 损伤阈值，器官病理学，行为定义，基因表达和神经病理学的基因型 爆炸暴露导致。值得注意的是，所有从本研究中得出的数据集将提供给 科学界为未来的分析和制定数据驱动的假设提供基础。 当前建议的研究将通过专家之间的长期合作来执行 传统和爆炸引起的TBI跨越下士Michael J. Crescenz（CMC）VA医疗中心和 宾夕法尼亚大学。总体而言，这项全面研究的执行将确定 有助于从TBI易感性，弹性和/或恢复的变化，因此将奠定基础 用于对未来机制的治疗剂研究，以钝化神经退行性后遗症并促进 Blast-TBI后的功能恢复。因此，这些研究将使我们的退伍军人长期健康受益 在CMC VA医疗中心，人口以及丰富了整体研究计划。