Molecular characterization of a rat model of chronic mild traumatic brain injury

慢性轻度创伤性脑损伤大鼠模型的分子特征

• 批准号: 10570159
• 负责人: TODD E WHITE
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10570159
• 关键词: Address; Animals; Anti-Inflammatory Agents; Anxiety; Behavior; Behavioral; Bioinformatics; Blood; Blood specimen; Brain Concussion; Characteristics; Chronic; Chronic Brain Injury; Development; Diagnosis; Diagnostic tests; Encephalitis; Exons; Experimental Animal Model; Experimental Models; Foundations; Gene Expression Profile; Genes; Goals; Human; Human Resources; Inflammation; Injury; Intravenous; Investigational Therapies; Laboratories; Learning; Memory; Mental Depression; Mentors; Methods; Military Personnel; Modeling; Molecular; Molecular Profiling; Morehouse School of Medicine; Neuregulin 1; Neuroprotective Agents; Outcome; Patients; Pattern; Performance; Plant Roots; Play; Pre-Clinical Model; Prevalence; Rattus; Research; Research Proposals; Role; Sample Size; Soldier; Stroke; Symptoms; Techniques; Testing; Therapeutic Trials; Time; Traumatic Brain Injury; Treatment Protocols; War; behavior test; behavioral outcome; chronic traumatic encephalopathy; contact sports; controlled cortical impact; diagnostic tool; experience; experimental study; forced swim test; improved; injured; innovation; mild traumatic brain injury; military veteran; morris water maze; neuroprotection; next generation sequencing; novel diagnostics; patient population; persistent symptom; precision medicine; predictive tools; targeted treatment; teacher; transcriptome; transcriptome sequencing

The proposed research will use a personalized precision medicine approach to establish a preclinical model of chronic repetitive mild traumatic brain injury (rmTBI). The first objective of the proposed research is the elucidation of the blood molecular signature for chronic rat rmTBI. The second objective is to test whether administration of the neuroprotective agent neuregulin-1 (NRG-1) improves behavioral performance in this model. This is highly relevant because a significant military and veteran population exists that experiences persistent symptoms chronically following mTBI/concussion. The Next Generation Sequencing (NGS) technique, RNA-Seq, can identify characteristic expression patterns of exons, or a molecular signature, in blood samples drawn from stroke and TBI patients that can distinguish the injured patients from controls. The proposed study will employ RNA-Seq analysis in the development of an experimental animal model that will allow for control of model parameters, reducing the sample size, compared to human studies, needed to conclusively identify blood molecular signatures. This represents a step towards the development of a diagnostic tool that could be used to objectively identify patients who suffered rmTBI, resulting more targeted treatment. A significant benefit of this preclinical model is that it will support testing of experimental therapies, giving valuable functional and blood molecular information in return. This proposal includes an initial therapeutic trial with NRG-1. NRG-1 has the additional ability to reduce brain inflammation which could address the issue of persistent inflammation that has been demonstrated in chronically injured brains. This could also contribute to the improvement of behavioral outcomes.

拟议的研究将使用个性化精准医学方法来建立临床前模型 慢性重复性轻度创伤性脑损伤（rmTBI）。拟议研究的第一个目标是 阐明慢性大鼠 rmTBI 的血液分子特征。第二个目标是测试是否 神经保护剂神经调节蛋白-1 (NRG-1) 的施用可改善此方面的行为表现 模型。这是高度相关的，因为存在大量的军人和退伍军人经历过 mTBI/脑震荡后长期出现持续症状。下一代测序 (NGS) RNA-Seq 技术可以识别外显子的特征表达模式或分子特征， 从中风和创伤性脑损伤患者中抽取血液样本，可以将受伤患者与对照组区分开来。这 拟议的研究将采用 RNA-Seq 分析来开发实验动物模型，该模型将 与人类研究相比，可以控制模型参数，减少样本量 最终鉴定血液分子特征。这标志着朝发展方向迈出了一步 诊断工具可用于客观识别患有 rmTBI 的患者，从而更有针对性 治疗。这种临床前模型的一个显着好处是它将支持实验疗法的测试， 作为回报，提供有价值的功能和血液分子信息。该提案包括初步 NRG-1 的治疗试验。 NRG-1 具有减少脑部炎症的额外能力，可以 解决慢性损伤大脑中已证实的持续炎症问题。这 也有助于改善行为结果。