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: 10438523
• 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/10438523
• 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; 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; brain dysfunction; 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 万军人中，约有 25% 报告称 遭受创伤性脑损伤 (TBI)。其中绝大多数都是温和的，而且在军队中， 由于暴露于各种来源的冲击波。不幸的是，有效的治疗 仍然需要，同时退伍军人应对大脑处理受损的长期影响 和神经退行性变。需要更好的理解来解决由以下原因引起的问题 创伤性脑损伤。神经元损伤易感性的遗传倾向与神经元损伤倾向的比较 神经保护弹性和修复代表了我们对神经保护的理解中尚未充分研究的差距 如何最好地治疗 TBI 后的大脑。此外，随着治疗方法变得越来越 个性化、深入了解遗传背景对 TBI 的影响 为了为受影响的退伍军人制定解决方案，复原力和恢复至关重要 将识别影响爆炸引起的功能损伤和损伤后程度的基因 通过研究一组模型小鼠品系来恢复，这些模型小鼠品系涵盖了几乎所有的遗传基因 实验室菌株之间的差异。损伤模型将利用完善的爆破管 旨在模拟现场爆炸爆炸过程中所经历的压力波的系统。一个 将在受伤前的基线上进行一系列行为测试，时间长达 30 爆炸暴露后几天，评估遗传学在功能恢复中的作用， 包括记忆表现、焦虑、运动协调、惊吓等不同方面 反应性和嵌套。我们还将比较 TBI 诱导的标记物区域特异性变化 神经退行性变和基因表达的改变。我们还将包括以下考试 其他器官因爆炸引起的损伤，看看遗传因素是否会影响其影响 非神经元组织。这项研究代表了对某些基因如何 影响爆炸引起的 TBI 和恢复。它将为未来提供重要的起点 研究以了解这些基因如何在受伤后的结果中发挥作用， 开发用于爆炸研究的最佳模型，并引导治疗的定义 可以调整的目标，以最终改善有历史的退伍军人的健康 爆炸曝光。