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.

美军在伊拉克和阿富汗发动的战争持续了十多年。在此期间，更多 超过240万美国军事人员被部署到阿富汗和伊拉克，为他们重复战斗 接触烈性炸药一直是家常便饭。烈性炸药的引爆会对大脑造成影响 多种方式造成的伤害。即使在没有直接钝器撞击头部的情况下 头部、主冲击波或爆炸超压(BOP)的明显加速/减速 由烈性炸药产生的物质会损伤大脑。越来越清楚的是，重复的 拳击手和足球运动员经历的轻度创伤性脑损伤与慢性脑损伤有关 创伤性脑病(CTE)，尸检证实为显著的tau和神经胶质病理改变； 它与其他几种慢性神经退行性疾病有重要的相似之处。重要的是，TBI 增加患阿尔茨海默病(AD)的风险。有越来越多的证据表明，重复爆炸 同样，暴露可能会使美国作战人员和退伍军人面临患上CTE的风险- 相关的神经退行性疾病。 因此，迫切需要更好地了解反复BOP引起的脑损伤的性质。 目前，轻度冲击波暴露在大脑中的机制和病理生理学还不是很清楚。 明白了。尤其是星形胶质细胞所起的作用--它在保护大脑免受中枢神经系统损害方面起着关键作用 侮辱--关于轻微冲击波引起的mTBI，我们基本上不知道。此外，两国之间的关系 BLAST诱导的病理性tau表达和星形胶质细胞病理仍有待进一步研究。我们的这些差距 机械论的理解目前阻碍了寻找新的方法来改善爆炸诱发的风险 MTBI从发展为进行性神经退行性疾病。 我们已经建立了一种BOP诱导的小鼠mTBI模型，该模型符合公认的和 经过验证的方法，可以准确地模拟与战场相关的露天爆炸。使用这种方法，我们 已发现证据表明，轻度冲击波暴露会导致病理相关的磷酸化tau蛋白增加和丢失 几种重要的星形细胞分子在预防中枢神经系统毒性方面发挥关键作用；特别是 谷氨酸转运体GLT-1/EAAT2、GLAST/EAAT1和谷氨酰胺合成酶(GS) 使谷氨酸解毒，并将其回收为谷氨酰胺。 在这个项目中，我们将检验以下假设：(I)温和的重复爆炸暴露会导致长时间的 星形胶质细胞功能的持久紊乱，损害大脑清除和代谢脑白质的能力 神经递质谷氨酸；(Ii)GLT-1/EAAT2的丢失将使大脑更容易受到冲击波的影响- 诱发tau病理，特别是在反复暴露防喷剂的情况下；(Iii)轻度冲击波暴露 诱导病理性星形细胞畸形，将使用实时活体成像进行研究 入路；以及(Iv)轻度重复冲击波诱导的星形细胞病变和tau病理将导致认知 和行为障碍。 成功完成这项提案的目标将提供对以下机制的新见解： 与反复冲击波相关的mTBI损害大脑，并有助于寻找新的策略来减少长时间的脑损伤。 与反复爆炸暴露相关的长期健康风险。