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: 9976341
• 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/9976341
• 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; 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确医学方法来建立临床前模型 慢性反复轻度创伤性脑损伤(RmTBI)。拟议研究的第一个目标是 慢性大鼠rmTBI血液分子特征的阐明。第二个目标是测试 神经保护剂神经调节素-1(NRG-1)的应用改善了这一模型的行为表现 模特。这是高度相关的，因为存在着大量的军人和退伍军人人口，他们经历了 脑损伤/脑震荡后的慢性持续性症状。下一代测序(NGS) RNA-Seq技术可以识别外显子的特征表达模式，或分子签名 取自中风和脑外伤患者的血液样本，可以区分受伤患者和对照组。这个 拟议的研究将使用RNA-Seq分析来开发一种实验动物模型，该模型将 允许控制模型参数，与人体研究相比，减少了样本大小，需要 最终确定血液分子特征。这代表着朝着开发 可用于客观识别患有rmTBI的患者的诊断工具，从而更具针对性 治疗。这一临床前模型的一个显著好处是它将支持实验疗法的测试， 提供有价值的功能和血液分子信息作为回报。这项提案包括一项初步的 NRG-1的治疗试验。NRG-1具有额外的减少脑部炎症的能力，这可能 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 也有助于改善行为结果。