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

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，超过240万名美国军事人员被部署到阿富汗和伊拉克，对他们来说，反复战斗暴露于烈性炸药是司空见惯的事情。烈性炸药的引爆可通过多种方式造成脑损伤。即使在飞行物体对头部没有直接钝性撞击或头部没有明显加速/减速的情况下，由烈性炸药产生的初级冲击波或爆炸超压(BOP)也能够损伤大脑。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脑损伤(MTBI)与慢性创伤性脑病(CTE)有关，尸检表明，慢性创伤性脑病有显著的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，脑外伤会增加患阿尔茨海默病(AD)的风险。越来越多的证据表明，重复爆炸暴露可能同样会使美国作战人员和退伍军人面临患上与CTE相关的神经退行性疾病的风险。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，轻微冲击波暴露对大脑的作用机制和病理生理学还不是很清楚。特别是，星形胶质细胞在保护大脑免受中枢神经系统侮辱方面所起的关键作用，在轻度冲击波诱导的mTBI方面，基本上是未知的。此外，冲击波诱导的病理性tau表达与星形胶质细胞病理之间的关系还有待进一步探讨。目前，我们在机械理解上的这些差距阻碍了寻找新的方法来改善冲击波诱导的mTBI发展为进行性神经退行性疾病的风险。我们已经建立了一种防喷剂诱导的mTBI的小鼠模型，该模型符合公认的、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，我们发现有证据表明，轻度冲击波暴露引起病理相关的磷酸化tau增加和几个重要的星形细胞分子的丢失，这些分子在预防中枢神经系统毒性中发挥关键作用，特别是谷氨酸转运体GLT-1/EAAT2，GLAST/EAAT1，以及负责解毒谷氨酸并将其循环为谷氨酰胺的谷氨酰胺合成酶(GS)。在本项目中，我们将检验下列假设：(I)轻度重复冲击波暴露会导致RIE星形胶质细胞功能长期受损，从而损害大脑清除和代谢神经递质谷氨酸的能力；(Ii)GLT-1/EAAT2的丢失将使大脑更容易受到冲击波诱导的tau病理的影响，尤其是在重复BOP暴露的情况下；(Iii)轻度重复冲击波暴露可诱导病理性星形细胞畸形，将使用实时体内成像方法对其进行研究；(Iv)轻度重复冲击波诱导的星形细胞和tau病理将引起认知和行为功能障碍。这项提案的目标的成功完成将为研究与重复冲击波相关的mTBI损害大脑的机制提供新的见解，并有助于寻找新的策略来减少与重复冲击波暴露相关的长期健康风险。

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.