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.

摘要 冲击波诱导的创伤性脑损伤(TBI)的神经学后果是我们面临的一个关键问题 退伍军人。脑外伤引起的认知障碍的影响可能是毁灭性的，但人们对其影响知之甚少。 由冲击波暴露引起的潜在独特的损伤机制引起的神经病理进展。 事实上，脑外伤可能会引发一系列持续数周、数月甚至数月的神经退行性改变。 然而，不同的遗传背景与易感性或 对冲击波引起的神经病理后遗症的抵抗力尚未建立。当前的目标是 该提案旨在解决知识方面的这一差距，并回应了最近关于 “冲击管致小鼠脑损伤的基因组分析”。我们建议对这一影响进行比较研究 8个品系(A/J、C57BL/6J、129S1/SvlmJ、NOD/LTJ、 NZO/HiLtJ、Ast/EIJ、PWK/PhJ和WSB/EIJ)，它们捕获了通常90%以上的遗传变异 用过的实验室小鼠。虽然主要目标是建立潜在的基因之间的关系 爆炸暴露的概况以及神经行为和神经病理后果，详细评估 还将进行多器官病理检查。首先，我们将建立致命性接触阈值和 每个菌株的多器官病理的范围和性质(目标1)。那么我们将使用多维电池 行为测试，以确定每种压力的认知和运动障碍的程度，最长可达1个月 在爆炸暴露后(目标2)。接下来，我们将在爆炸后的离散时间点执行深度量化 数百个相关基因的基因表达变化与神经病理后遗症分析 使用传统的免疫组织化学以及尖端成像质谱学能够 同时量化多达37种蛋白质的水平(目标3)。最后，我们将进行详细的统计 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分型 是爆炸暴露造成的。值得注意的是，这项研究得出的所有数据集都将提供给 科学界为未来分析和提出数据驱动的假设提供基础。 目前拟议的研究将通过以下专家之间的长期合作来执行 迈克尔·J·克雷森兹下士(CMC)退伍军人医学中心和 宾夕法尼亚大学。总体而言，这项全面研究的执行将确定 有助于改变敏感性、恢复力和/或从脑损伤中恢复，从而奠定基础 用于未来基于机制的治疗剂研究，以钝化神经退行性后遗症并促进 冲击性脑损伤后的功能恢复。因此，这些研究将有利于我们退伍军人的长期健康 并丰富了CMC退伍军人医学中心的整体研究计划。