Building translationally relevant relationships between neuropathology and abnormal neuroimaging in Veterans and mechanisms of blast-induced neurotrauma in mice

建立退伍军人的神经病理学和异常神经影像以及小鼠爆炸引起的神经创伤机制之间的转化相关关系

基本信息

批准号：
10082417
负责人：
David G Cook
金额：
--
依托单位：
VA PUGET SOUND HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-10-01 至 2022-12-31
项目状态：
已结题

项目摘要

Blast exposure is a common experience of Operation Iraqi Freedom/Operation Enduring Freedom/ Operation New Dawn (OIF/OEF/OND) Veterans. There is growing concern that repetitive blast exposure may be a risk factor for neurological disorders, including chronic traumatic encephalopathy (CTE). The pathogenic processes that link early-occurring, often transient brain injuries, to subsequent chronic behavioral and cognitive impairments are not well understood. The pathology underlying these impairments is poorly understood. A number of important knowledge gaps currently impede progress toward elucidating the patho- physiology of repetitive blast-related mTBI that include, limited insight into the translational significance of the pathology produced in blast-induced animal TBI models with reference to neuroimaging findings in Veterans with blast-related mTBI. Moreover, the very limited neuropathological information from such Veterans significantly limits our understanding of blast-related mTBI. Adding to the complexity of this issue numerous research groups have reported multiple forms of blast- induced pathology in a number of animal blast TBI models including: aberrant tau expression, reactive astrocytosis, microgliosis, axonal injury, myelin damage, and blood-brain barrier (BBB) disruption. Much attention has been placed on tau because of its close association with sports-related CTE. Whether repetitive blast-related mTBI follows that same pathogenic pathway to CTE, which is defined chiefly by specific tau deposits, remains an open question. However, recent findings call attention to prominent glial pathology in Veterans with blast-related mTBI, raising the possibility that this form of neurotrauma may represent a distinct class; or possibly a distinct pathogenic process leading to chronic mTBI (which also may involve tau pathology). In repetitive blast exposed mice we have found microglial and astroglial pathology that, especially in subcortical regions of the brain, is quite similar to the white matter-associated glial pathology recently reported in Veterans with blast-related mTBI. We also have evidence that discrete microdomains of early-occurring BBB disintegrity are closely associated with aberrant microglial responses that include myelin phagocytosis, astrogliosis, and neuron loss. These data have prompted us test four closely related hypotheses: Specific Aim 1: will test the hypothesis that in blast exposed mice, specific brain regions are vulnerable to early-occurring blood-brain barrier (BBB) disruption; and that these disruptions may trigger later persistent pathology associated with myelin disruption, as well as axonal and neuronal injury. Specific Aim 2: will test the hypothesis that in mice, white matter pathology involving glial-mediated myelin phagocytosis and axonal injury will be closely associated with reduced fractional anisotropy. Specific Aim 3: will test the hypothesis that specific brain regions with myelin, axonal injury, and BBB disrupt- tion in mice will correspond to DTl neuroimaging findings in similar brain regions in Veterans with blast- related mTBI. Specific Aim 4: will test the hypothesis that neuropathology findings in brains from Veterans with blast-related mTBI will be found in the same anatomical regions as those identified by neuroimaging in living Veterans and will correspond with the pathology in blast-exposed mice. Successful completion of these aims will: (i) facilitate progress toward understanding the pathogenic cascades leading to chronic behavioral and cognitive impairments in Veterans with blast-related mTBI; and (ii) refine the translational relevance of animal blast TBI models needed to improve their usefulness as tools to speed the search for strategies to treat and prevent chronic blast-related neurodegeneration.

爆炸暴露是伊拉克自由行动/持久自由行动的常见经历/ 行动新黎明（OIF/OEF/OND）退伍军人。人们越来越担心重复的爆炸暴露可能成为神经系统疾病的危险因素，包括慢性创伤性脑病（CTE）。致病性将早期发生（通常是短暂脑损伤）与随后的慢性行为和认知障碍尚不清楚。这些障碍的基础病理很差理解。目前，许多重要的知识差距阻碍了阐明病情的进展重复性爆炸相关的MTBI的生理学，其中包括对转化意义的有限见解在爆炸诱导的动物TBI模型中产生的病理学，参考了退伍军人的神经影像学发现与爆炸有关的mTBI。此外，从此类退伍军人那里的神经病理学信息非常有限显着限制了我们对爆炸相关的MTBI的理解。除此问题的复杂性外，许多研究小组都报告了多种形式的爆炸许多动物爆炸TBI模型中诱导的病理学，包括：异常Tau表达，反应性星形细胞增多症，小胶质细胞增多，轴突损伤，髓鞘损伤和血脑屏障（BBB）破坏。很多由于与运动相关的CTE有着密切的关联，因此注意力引起了人们的注意。是否重复与爆炸有关的MTBI遵循相同的致病途径到CTE，主要由特定的tau定义存款，仍然是一个悬而未决的问题。然而，最近的发现呼吁人们注意与爆炸相关的MTBI的退伍军人的显着神经病理学，提高这种形式的神经特征可能代表一个独特的阶级的可能性。或可能是独特的致病过程导致慢性MTBI（也可能涉及TAU病理学）。在重复的爆炸暴露小鼠中，我们发现了小胶质细胞和星形胶质细胞病理学，尤其是在大脑的皮层下区域与最近报道的白质相关的神经胶质病理非常相似在与爆炸相关的MTBI的退伍军人中。我们还有证据表明早期出现的BBB的离散微区域崩解与异常的小胶质细胞反应密切相关，包括髓鞘吞噬作用，星形胶质病和神经元丧失。这些数据促使我们检验了四个密切相关的假设：特定目的1：将检验以下假设：在爆炸暴露的小鼠中，特定的大脑区域容易受到影响早期血脑屏障（BBB）破坏；这些干扰可能会触发以后的持久性与髓磷脂破坏以及轴突和神经元损伤相关的病理。特定目的2：将检验以下假设：在小鼠中，涉及神经胶质介导的髓磷脂的白质病理学吞噬作用和轴突损伤将与分数各向异性降低密切相关。特定目的3：将检验以下假设：特定的大脑区域患有髓磷脂，轴突损伤和BBB扰动 - 小鼠中的TIN将对对应于Blast的退伍军人中相似大脑区域的DTL神经影像学发现相关的mtbi。特定目的4：将检验以下假设：与爆炸有关的退伍军人的大脑中的神经病理学发现 MTBI将在与活着的退伍军人和神经影像相同的解剖区域中找到将与暴露于爆炸的小鼠中的病理相对应。这些目标的成功完成将：（i）促进理解致病性的进步级联导致与爆炸有关的MTBI的退伍军人的慢性行为和认知障碍；（ii）完善动物爆炸TBI模型的翻译相关性，以提高其用作工具的用途加快搜索治疗和预防慢性爆炸相关神经变性的策略。