The role of glia dysfunction in the neurodegenerative processes induced by blast

神经胶质细胞功能障碍在爆炸引起的神经退行性过程中的作用

• 批准号: 8633554
• 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
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633554
• 关键词: Ablation; Acceleration; Address; Affect; Afghanistan; Alzheimer' s Disease; Animal Model; Astrocytes; Autopsy; Behavioral; Blast Cell; Brain; Brain Injuries; Brain region; Chromosomes, Human, Pair 17; Chronic; Cleaved cell; Cognitive; Conflict (Psychology); Confocal Microscopy; Deceleration; Dementia; Development; Devices; Dysmorphology; Environmental Risk Factor; Explosion; Exposure to; FTD with parkinsonism; Face; Flying body movement; Frontotemporal Dementia; Functional disorder; GLAST Protein; Genetic; Gliosis; Glutamate Transporter; Glutamate-Ammonia Ligase; Glutamates; Glutamine; Goals; Head; Health; Hour; Impaired cognition; Injury; Iraq; Lasers; Link; Long-Term Effects; Manufactured football; Measures; Military Personnel; Modeling; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neurotransmitters; Parkinsonian Disorders; Pathologic; Pathology; Performance; Play; Predisposition; Prevalence; Process; Recycling; Risk; Risk Factors; Role; Services; Severities; Shock; Testing; Time; Toxic effect; Trauma; Traumatic Brain Injury; Tube; Veterans; Wages; War; Work; combat; corticobasal degeneration; experience; hyperphosphorylated tau; in vivo; in vivo imaging; injured; insight; member; mouse model; nervous system disorder; neuronal cell body; prevent; public health relevance; tau Proteins; tau expression; two-photon

The wars waged by the US forces in Iraq and Afghanistan span more than a decade. Over this period more than 2.4 million US military personnel have deployed to Afghanistan and Iraq and for whom repetitive combat exposure to high explosives has been a common occurrence. Detonation of high explosives can inflict brain injury by multiple means. Even in the absence of direct blunt impacts to the head from flying objects or appreciable acceleration/deceleration of the head, the primary shock wave or blast overpressure (BOP) generated by high explosives is capable of injuring the brain. It is becoming increasingly clear that repetitive mild traumatic brain injury (mTBI) experienced by boxers and football players is associated with chronic traumatic encephalopathy (CTE) that is evidenced upon autopsy by significant tau and glial pathology; and which shares important similarities to several other chronic neurodegenerative diseases. Importantly, TBI increases the risk of developing Alzheimer's disease (AD). There is growing evidence that repetitive blast exposure may similarly place US combat service members and Veterans at risk for also developing CTE- related neurodegenerative disorders. Thus, there is an urgent need to better understand the nature of brain injuries caused by repetitive BOP. Currently, the mechanisms and pathophysiology underlying mild blast exposure on the brain are not well- understood. In particular the role played by astrocytes-which are crucial in protecting the brain from CNS insults-is largely unknown with regards to mild blast-induced mTBI. In addition, the relationship between blast-induced pathologic tau expression and astrocyte pathology remains to be explored. These gaps in our mechanistic understanding currently impede the search for new ways to ameliorate the risk of blast-induced mTBI from developing into a progressive neurodegenerative disorder. We have established a murine model of BOP-induced mTBI that is in keeping with well-established and validated approaches that accurately mimics battlefield-relevant open-field explosions. Using this approach we have found evidence that mild blast exposure provokes increased pathologically-related phospho-tau and loss of several important astrocytic molecules that play critical roles in preventing CNS toxicity; specifically the glutamate transporters GLT-1/EAAT2, GLAST/EAAT1, and glutamine synthetase (GS) that is responsible for detoxifying glutamate and recycling it into glutamine. In this project we will test the following hypotheses: (i) that mild repetitive blast exposure give rise to long lasting disturbances in astrocyte function that impair the ability of the brain to clear and metabolize the neurotransmitter glutamate; (ii) that loss of GLT-1/EAAT2 will render the brain more susceptible to blast- induced tau pathology, particularly in the context of repetitive BOP exposures; (iii) that mild blast exposure induces pathologic astrocytic dysmorphology that will be investigated using real-time in vivo imaging approaches; and (iv) that mild repetitive blast-induced astrocytic and tau pathology will give rise to cognitive and behavioral dysfunction. Successful completion of the aims of this proposal will provide new insights into the mechanisms by which repetitive blast-related mTBI harms the brain and facilitate the search for new strategies to reduce the long- term health risks associated with repetitive blast exposure.

十多年来，美军在伊拉克和阿富汗发动的战争跨越了十多年。在此期间更多 超过240万美国军事人员已部署到阿富汗和伊拉克，并为此重复战斗 暴露于高炸药一直是很普遍的情况。高爆炸物的爆炸会导致大脑 通过多种方式受伤。即使在没有直接钝的情况下，也会因飞行物体或 头部的明显加速/减速，主要冲击波或爆炸过压（BOP） 高爆炸物产生的能够伤害大脑。重复的越来越清楚 拳击手和足球运动员经历的轻度创伤性脑损伤（MTBI）与慢性有关 创伤性脑病（CTE）在尸检时被明显的tau和神经胶质病理证明；和 它与其他几种慢性神经退行性疾病具有重要的相似性。重要的是，TBI 增加患阿尔茨海默氏病（AD）的风险。越来越多的证据表明重复性爆炸 曝光可能会使美国战斗服务成员和退伍军人面临发展CTE的风险 相关的神经退行性疾病。 因此，迫切需要更好地理解由重复BOP造成的脑损伤的性质。 目前，大脑中的轻度爆炸性暴露的机制和病理生理学不是很好 理解。特别是星形胶质细胞所起的作用，这对于保护大脑免受CNS至关重要 侮辱 - 在轻度爆炸引起的MTBI方面，基本上未知。另外， 爆炸诱导的病理TAU表达和星形胶质细胞病理学仍有待探索。这些差距 机械理解目前阻碍了改善爆炸诱导风险的新方法 MTBI从发展为进行性神经退行性疾病。 我们已经建立了一个由BOP引起的MTBI的鼠模型，该模型与建立完善的和 经过验证的方法，可以准确地模仿与战场相关的开放式爆炸。使用这种方法我们 已经发现的证据表明，温和的爆炸性暴露会增加病理相关的磷酸化和损失 在几个重要的星形细胞分子中，它们在预防中枢神经系统毒性中起着关键作用；特别是 谷氨酸转运蛋白GLT-1/EAAT2，GLAST/EAAT1和谷氨酰胺合成酶（GS） 排毒谷氨酸并将其回收到谷氨酰胺中。 在这个项目中，我们将测试以下假设：（i）轻度重复的爆炸暴露会产生长时间 星形胶质细胞功能的持久干扰损害了大脑清除和代谢的能力 神经递质谷氨酸； （ii）GLT-1/EAAT2的丧失会使大脑更容易受到爆炸的影响 - 诱发的tau病理学，特别是在重复的BOP暴露的背景下； （iii）轻度爆炸暴露 诱导将使用实时体内成像研究的病理星形胶质细胞畸形学 方法； （iv）轻度重复的爆炸诱导的星形胶质细胞和tau病理学会引起认知 和行为功能障碍。 成功完成该提案的目标将为您提供有关机制的新见解 与重复的爆炸相关的MTBI会损害大脑，并促进寻找新策略以减少长期 与重复爆炸有关的任期健康风险。