Blood-Brain Barrier Disruption in Blast Neurotrauma

爆炸性神经外伤中的血脑屏障破坏

基本信息

批准号：
8510482
负责人：
Amanda Dawn Gaudreau-Balderrama
金额：
$ 3.98万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8510482
关键词：
Ablation Acute Address Affect Afghanistan Algorithms Alzheimer&apos s Disease Area Astrocytosis Autopsy Biological Models Biomechanics Biomedical Research Blast Cell Blood - brain barrier anatomy Boston Brain Brain Edema Brain Injuries Brain region C57BL/6 Mouse Calibration Case Series Cells Cerebral cortex Cessation of life Characteristics Chronic Collaborations Conflict (Psychology)Craniocerebral Trauma Data Development Diagnostic Diffuse Disease Doctor of Philosophy Dose Fractionation Electrical Engineering Evans blue stain Experimental Pathology Exposure to Extravasation Fiber Goals Gold Harvest Head Hippocampus (Brain)Image Injury Iraq Lasers Link Maps Mass Spectrum Analysis Methods Military Personnel Modeling Morbidity - disease rate Mus Nerve Degeneration Neurodegenerative Disorders Noise Pathogenesis Pathology Pattern Play Protocols documentation Reporting Research Resolution Role Software Tools Staging Structure Techniques Technology Testing Therapeutic Time Trace Elements Traumatic Brain Injury Ultrastructural Pathology United States National Institutes of Health Universities Validation Veterans Visualization software War Woman Work analytical tool authority axonopathy design disability improved innovative technologies insight interest male medical schools nanoparticle neuroinflammation neuropathology neurophysiology neuropsychiatry research study response tau Proteins tau aggregation tool young adult

项目摘要

DESCRIPTION (provided by applicant): Blast-related traumatic brain injury (TBI), the "signature injury" of the Iraq and Afghanistan wars, affects 12- 23% of the 2.2 million U.S. servicemen and women deployed in these conflicts. Untold thousands of civilians are also affected in these and other conflict areas around the world. Blast exposure is a recognized precipitant of acute neurotrauma and secondary neuropsychiatric morbidity, including chronic traumatic encephalopathy (CTE). First reported in athletes with repetitive head injury, CTE is a tau protein-linked neurodegenerative disease with a distinctive pattern of perivascular phospho-tau pathology, disseminated microgliosis and astrocytosis, diffuse axonopathy, and widespread cortical neurodegeneration. Recent research conducted by our collaborative team at Boston University School of Medicine, NIH Alzheimer's Disease Center, and Boston VA has revealed evidence of early CTE neuropathology in the first case series of postmortem brains from blast-exposed U.S. military veterans. In addition, we have replicated CTE neuropathology and neurophysiological deficits in blast-exposed mice. Ultrastructural analysis of brains from blast-exposed mice demonstrated pervasive perivascular pathology, including disruption of blood-brain barrier (BBB) cytoarchitecture. Ongoing studies indicate that blast exposure induces focal BBB disruption in specific brain regions and structures vulnerable to CTE neuropathology. We hypothesize that blast exposure focally disrupts BBB structural organization and functional integrity leading to chronic neuroinflammation and neuropathological sequelae, including CTE. To test this hypothesis, we will use high-resolution metallomic imaging mass spectrometry (MIMS) to map BBB disruption as a function of blast exposure and CTE-linked neuropathology. This project will implement purpose-designed algorithms and software tools to analytically map focal BBB integrity across the brain at single-cell spatial resolution. Calibrated MIMS protocols will be used to localize and quantitate extravasation of systemically administered BBB-impermeable nanoreporter probes indicative of focal BBB disruption. These tools will be used in our validated murine blast neurotrauma model to evaluate temporal and regional patterns of BBB disruption as a function of blast dose, fractionation, and post-exposure interval. Results will be compared to BBB disruption patterns detected by conventional methods (Evans blue, HRP, brain edema) and correlated with pericapillary ultrastructural pathology and CTE- linked neuropathology. The results of these studies will advance understanding of fundamental mechanisms of brain injury in blast neurotrauma and provide critical information regarding the role of the BBB and microvascular disruption in the pathogenesis of blasted-related TBI and late-emerging sequelae, including CTE. Insights gained from this work will stimulate further development of MIMS technology for biomedical research and accelerate translational development of urgently needed diagnostics and therapeutics for blast-related TBI and CTE.

描述（由申请人提供）：与爆炸有关的创伤性脑损伤（TBI），伊拉克和阿富汗战争的“签名伤害”影响了在这些冲突中部署的220万美国军人和妇女中的12％。在世界各地这些和其他冲突地区，成千上万的平民也受到影响。爆炸暴露是公认的急性神经曲和次生神经精神病发病率的抑制剂，包括慢性创伤性脑病（CTE）。 CTE首次在患有重复头部损伤的运动员中首次报道了TAU蛋白连接的神经退行性疾病，具有独特的周围磷酸化病理学，散布的小胶质细胞增多和星形胶质细胞增多，弥漫性轴突性疾病，以及广泛的皮质神经变性。我们的合作团队在波士顿大学医学院，NIH阿尔茨海默氏病中心和弗吉尼亚州波士顿的合作团队进行的最新研究揭示了早期CTE神经病理学的证据，这是第一个病后大脑的第一个病后大脑，来自爆炸暴露的美国军事退伍军人。此外，我们在暴露于爆炸的小鼠中复制了CTE神经病理学和神经生理缺陷。对爆炸暴露小鼠的大脑的超微结构分析表明，血管周围病理普遍存在，包括破坏血脑屏障（BBB）的细胞结构结构。正在进行的研究表明，在特定的大脑区域和容易受到CTE神经病理学的结构中，爆炸暴露会导致局灶性BBB破坏。我们假设爆炸暴露会局部破坏BBB结构组织和功能完整性，从而导致慢性神经炎症和神经病理后遗症，包括CTE。为了检验这一假设，我们将使用高分辨率金属成像质谱法（MIMS）来映射BBB的破坏，这是爆炸暴露和CTE连接神经病理学的函数。该项目将通过单细胞空间分辨率来分析大脑的焦点BBB完整性。校准的MIMS协议将用于定位和定量系统施用的BBB可渗透纳米培养剂探针，指示局灶性BBB破坏。这些工具将用于我们经过验证的Murine Blast Neurotrauma模型，以评估BBB破坏的时间和区域模式，这是爆炸剂量，分级和暴露后间隔的函数。结果将将常规方法（Evans Blue，HRP，脑水肿）检测到的BBB破坏模式进行比较，并与周围毛细血管超微结构病理学和CTE连接的神经病理相关。这些研究的结果将提高对BLAST神经肿瘤中脑损伤的基本机制的了解，并提供有关BBB和微血管破坏在包括CTE在内的爆炸相关TBI和晚期出现后被频为发病机理中的作用的关键信息。从这项工作中获得的见解将刺激MIMS技术的进一步开发，用于生物医学研究，并加速了与爆炸相关的TBI和CTE的急需诊断和治疗学的转化开发。