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: 10092813
• 负责人: Bruce A. Citron
• 金额: --
• 依托单位: VA NEW JERSEY HEALTH CARE SYSTEM
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092813
• 关键词: Address; Affect; Anxiety; Behavior; Behavioral; Biochemistry; Blast Injuries; Blood; Blood - brain barrier anatomy; Brain; Brain Injuries; Cells; Disease; Exposure to; Eye; Foundations; Future; Gastrointestinal tract structure; Gene Expression; Genes; Genetic; Genetic Drift; Genetic Predisposition to Disease; Genetic Variation; Genomics; Genotype; Health; Histologic; Human Resources; Impairment; Individual; Inflammatory; Injury; International; Investigation; Kidney; Laboratories; Lead; Liver; Long-Term Effects; Lung; Memory; Messenger RNA; Military Personnel; Modeling; Molecular; Motor; Mouse Strains; Mus; Nerve Degeneration; Neuroglia; Neurons; Organ; Outcome; Pattern; Performance; Play; Positioning Attribute; Predisposition; Quantitative Reverse Transcriptase PCR; Recording of previous events; Recovery; Recovery of Function; Reporting; Research; Research Personnel; Resistance; Role; Services; Sex Differences; Source; Spleen; System; TBI treatment; Testing; Therapeutic; Tissue-Specific Gene Expression; Tissues; Traumatic Brain Injury; Traumatic Brain Injury recovery; Tube; Veterans; Western Blotting; Work; base; behavior test; behavioral outcome; blast exposure; cognitive performance; design; effective therapy; experience; experimental study; functional disability; functional outcomes; genetic information; improved; injury recovery; instrument; instrumentation; military veteran; mouse model; pressure; repaired; resilience; resistant strain; response; response to injury; sex; therapeutic target; transcriptome sequencing; traumatic event

Approximately 25% of the two million service personnel deployed since 2000 have reported receiving a traumatic brain injury (TBI). The vast majority of these are mild, and, in the military, due to exposure to blast waves from a variety of sources. Unfortunately, an effective treatment is still needed, meanwhile Veterans cope with long-term effects of impaired brain processing and neurodegeneration. A better understanding is needed to address the problems caused by TBI. Genetic predispositions to neuronal damage susceptibility versus predispositions to neuroprotective resilience and repair represent a understudied gap in our understanding of how to best treat the brain following a TBI. Moreover, as therapeutic approaches become more personalized, a robust understanding of the contributions of genetic background to TBI resilience and recovery is essential in order to develop solutions for our affected Veterans We will identify genes that affect the degree of blast-induced functional impairment and post-injury recovery by studying a set of model mouse strains that encompass most all of the genetic variations between laboratory strains. The injury model will utilize a well-established blast tube system designed to mimic pressure waves experienced during a field explosive detonation. A battery of behavioral tests will be performed at baseline prior to the injury and as long as 30 days after blast exposure to assess the role of genetics in recovery of functional outcomes, including different aspects of memory performance, anxiety, motor coordination, startle reactivity, and nesting. We will also compare TBI-induced region specific changes in markers of neurodegeneration and alterations in gene expression. We will also include examinations of other organs for blast-induced damage to see if the genetic factors influence the affects upon non-neuronal tissue. This research represents a multi-level examination of how certain genes influence blast-induced TBI and recovery. It will provide essential starting points for future investigations to understand how these genes play roles in the post-injury outcomes, to develop optimal models for blast studies, and to lead towards the definition of therapeutic targets that could be modulated to eventually improve the health of Veterans with histories of blast exposures.

自2000年以来部署的200万名服务人员中，约25%的人报告说 接受创伤性脑损伤(TBI)。其中绝大多数是温和的，在军队中， 由于暴露在各种来源的冲击波中。不幸的是，一个有效的治疗方法 仍然需要，同时退伍军人应对大脑处理能力受损的长期影响 和神经退化。需要更好地理解，以解决由 TBI。神经细胞损伤的遗传易感性与易感性 神经保护的恢复力和修复是我们对 如何最好地治疗脑外伤后的大脑。此外，随着治疗方法变得越来越多 对遗传背景对脑损伤的贡献有一个个性化的、强有力的理解 为了为我们受影响的退伍军人制定解决方案，适应力和恢复是必不可少的 将确定影响冲击波引起的功能损害程度和损伤后程度的基因 通过研究一组包含几乎所有基因的模型小鼠品系来恢复 实验室菌株之间的变异。损伤模型将使用已建立好的爆炸管 用于模拟野外爆炸过程中经历的压力波的系统。一个 一连串的行为测试将在受伤前的基线上进行，长达30 在爆炸暴露几天后评估遗传学在功能结果恢复中的作用， 包括不同方面的记忆表现、焦虑、运动协调、惊吓 反应性和嵌套性。我们还将比较脑损伤引起的区域特异性标志物的变化 神经退化和基因表达的改变。我们还将包括以下考试： 看看遗传因素是否会影响冲击波对其他器官的损伤 非神经性组织。这项研究代表了对某些基因如何 影响冲击性脑损伤的发生和恢复。它将为未来提供必要的起点 调查以了解这些基因如何在受伤后的结果中发挥作用， 开发BLAST研究的最佳模型，并导致治疗性的定义 可以调整以最终改善有以下病史的退伍军人健康的目标 爆炸曝光。