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: 10438522
• 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/10438522
• 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; Immunohistochemistry; Incidence; Injury; Intestines; Kidney; Knowledge; Laboratory mice; Learning; Lung; Measures; Medical center; Memory; Motor; Mouse Strains; Mus; Nature; Nerve Degeneration; Neurologic; Organ; Pathologic; Pathologist; Pathology; Pennsylvania; 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; blast exposure; body system; discrete time; functional restoration; improved; mass spectrometric imaging; military veteran; 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一个关键问题 退伍军人脑损伤引起的认知缺陷的影响可能是毁灭性的，但人们对此知之甚少。 由爆炸暴露引起的潜在独特损伤机制引发的神经病理进展。 事实上，TBI 可能会引发一系列神经退行性变化，持续数周、数月甚至数周。 然而，不同遗传背景与易感性之间的关系或 目前尚未确定对爆炸引起的神经病理学后遗症的恢复力的目标。 该提案旨在解决这一知识差距，并响应最近的申请请求 “对小鼠爆管诱发 TBI 的基因组分析”，我们建议对其效果进行比较研究。 八种小鼠品系（A/J、C57Bl/6J、129S1/SvlmJ、NOD/LtJ、 NZO/HiLtJ、Ast/EiJ、PWK/PhJ 和 WSB/EiJ）捕获了常见基因组中 90% 以上的遗传变异 使用实验室小鼠，主要目标是建立潜在遗传之间的关系。 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检查，首先，我们将建立致死暴露阈值和阈值。 每种菌株的多器官病理学的程度和性质（目标 1）然后我们将使用多维电池。 长达 1 个月的行为测试，以确定每种菌株的认知和运动缺陷程度 接下来，在爆炸后的离散时间点，我们将执行深入的定量分析。 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法能够 同时量化多达 37 种蛋白质的水平（目标 3）。 测试，包括主成分分析，以确定各种潜在因素的相对贡献 损伤阈值、器官病理学、行为缺陷、基因表达和神经病理学的基因型 值得注意的是，本研究得出的所有数据集都将提供给 科学界为未来分析和制定数据驱动假设奠定基础。 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 横跨迈克尔·J·克雷森兹 (Michael J. Crescenz) 下士 (CMC) VA 医疗中心和 总体而言，这项综合研究的执行将确定以下基因： 有助于 TBI 的易感性、恢复力和/或恢复的变化，从而奠定基础 用于未来基于机制的治疗药物研究，以减轻神经退行性后遗症并促进 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 CMC VA 医疗中心的整体研究项目。