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: 9768240
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768240
• 关键词: Address; Animals; Anti-inflammatory; Anxiety; Behavior; Behavioral; Bioinformatics; Blood; Blood specimen; Brain Concussion; Brain Injuries; Characteristics; Chronic; Development; Diagnosis; Diagnostic; 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; Population; Pre-Clinical Model; Prevalence; Rattus; Research; Research Proposals; Role; Sample Size; Soldier; Sports; Stroke; Symptoms; Techniques; Testing; Therapeutic Trials; Time; Traumatic Brain Injury; Treatment Protocols; Veterans; War; behavior test; behavioral outcome; chronic traumatic encephalopathy; controlled cortical impact; experience; experimental study; forced swim test; improved; injured; innovation; mild traumatic brain injury; morris water maze; neuroprotection; next generation sequencing; novel diagnostics; patient population; persistent symptom; precision medicine; targeted treatment; teacher; tool; 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）的给药改善了这种情况下的行为表现。 模型这是高度相关的，因为存在大量的军事和退伍军人， mTBI/脑震荡后长期持续症状。下一代测序（NGS） RNA-Seq技术可以鉴定外显子的特征性表达模式或分子标记， 从中风和TBI患者中抽取的血液样本可以将受伤的患者与对照区分开来。的 拟议的研究将采用RNA-Seq分析来开发实验动物模型， 允许控制模型参数，与人体研究相比，减少样本量， 确定血液分子特征这是朝着发展一种 诊断工具，可用于客观地识别患有rmTBI的患者，从而更有针对性地 治疗这种临床前模型的一个显著好处是，它将支持实验疗法的测试， 从而提供有价值的功能和血液分子信息。该提案包括一项初步的 NRG-1的治疗试验NRG-1具有减少大脑炎症的额外能力， 解决在慢性损伤的大脑中已经证明的持续性炎症的问题。这 也可以有助于改善行为结果。