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: 9275411
• 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/9275411
• 关键词: Ablation; Acceleration; Address; Affect; Afghanistan; Alzheimer' s Disease; Anatomy; Animal Model; Astrocytes; Autopsy; Behavioral; Blast Cell; Brain; Brain Injuries; Brain region; Cells; 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; Functional disorder; GLAST Protein; Genetic; Gliosis; Glutamate Transporter; Glutamate-Ammonia Ligase; Glutamates; Glutamine; Goals; Head; Health; Hour; Impaired cognition; Impairment; Injury; Iraq; Lasers; Link; Long-Term Effects; Manufactured football; Measures; Military Personnel; Modeling; Multiple Trauma; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neurotransmitters; 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; behavioral impairment; chronic traumatic encephalopathy; combat; corticobasal degeneration; experience; hyperphosphorylated tau; imaging approach; in vivo; in vivo imaging; insight; mild traumatic brain injury; mouse model; nervous system disorder; prevent; public health relevance; service member; tau Proteins; tau expression; two-photon

DESCRIPTION (provided by applicant): 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 bran 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 rie to long lasting disturbances in astrocyte function that impair the ability of the brain to clear an 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.

描述（由申请人提供）： 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，有240多万美国军事人员部署到阿富汗和伊拉克，对他们来说，反复接触高爆炸物是家常便饭。烈性炸药的爆炸可以通过多种方式造成脑损伤。即使没有飞行物体对头部的直接钝击或头部的明显加速/减速，高能炸药产生的初级冲击波或爆炸超压（BOP）也能够伤害大脑。越来越清楚的是，拳击手和足球运动员经历的重复性轻度创伤性麸皮损伤（mTBI）与慢性创伤性脑病（CTE）相关，这在尸检时通过显著的tau和神经胶质病理学得到证实;并且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会增加患阿尔茨海默病（AD）的风险。越来越多的证据表明，重复的爆炸暴露可能同样使美国战斗服务成员和退伍军人处于发展CTE相关神经退行性疾病的风险之中。 因此，迫切需要更好地了解重复BOP引起的脑损伤的性质。目前，轻度冲击波暴露对大脑的作用机制和病理生理学还不清楚.特别是星形胶质细胞在保护大脑免受CNS损伤方面所起的作用在很大程度上是未知的。此外，胚细胞诱导的病理性tau蛋白表达与星形胶质细胞病理学之间的关系仍有待探讨。目前，我们对机制理解的这些差距阻碍了寻找新的方法来改善爆炸诱导的mTBI发展为进行性神经退行性疾病的风险。 我们已经建立了BOP诱导的mTBI的小鼠模型，该模型与准确模拟战场相关的露天爆炸的成熟和验证的方法一致。使用这种方法，我们已经发现证据表明，轻度爆炸暴露引起病理相关的磷酸化tau蛋白增加和几种重要的星形胶质细胞分子的损失，这些分子在预防CNS毒性中起关键作用;特别是谷氨酸转运蛋白GLT-1/EAAT 2，GLAST/EAAT 1和谷氨酰胺合成酶（GS），负责将谷氨酸解毒并将其再循环为谷氨酰胺。 在该项目中，我们将测试以下假设：（i）轻度重复冲击波暴露使星形胶质细胞功能长期受到干扰，这损害了大脑清除和代谢神经递质谷氨酸的能力;（ii）GLT-1/EAAT 2的丧失将使大脑更容易受到冲击波诱导的tau病理学的影响，特别是在重复BOP暴露的情况下;（iii）轻度冲击波暴露诱导病理性星形胶质细胞畸形，其将使用实时体内成像方法进行研究;和（iv）轻度重复冲击波诱导的星形胶质细胞和tau病理将引起认知和行为功能障碍。 成功完成本提案的目标将为重复性爆炸相关mTBI损害大脑的机制提供新的见解，并促进寻找新的策略来减少与重复性爆炸暴露相关的长期健康风险。