Prevention of Hemorrhage and Death After Traumatic Blast Injury (TBI)

描述（由申请人提供）： 摘要爆炸性爆炸引起的创伤性脑损伤（TBI）和器官多发性创伤已被确定为目前伊拉克和阿富汗军事交战中最常见的死亡和受伤原因，高达20%的退伍军人返回美国经历了某种形式的TBI。战场条件下的爆炸冲击波暴露可导致严重神经功能障碍的超急性和急性症状，这是由于爆炸引起的神经元和脑血管的剪切损伤。暴露于冲击波可导致休克的立即发展，并经常导致快速死亡或慢性失能，这就要求更积极地开发TBI的新型诊断和治疗模式。 我们在小鼠中开发了冲击波诱导的TBI的实验模型，并证明暴露于冲击波的实验小鼠具有先前在人类患者中报道的许多特征，例如视觉功能下降，前庭功能异常和学习能力受损。在这项提案中，我们计划进一步扩大我们的研究，并解决以下具体目标：我们将通过使用功能，结构，分子和行为为基础的测试电池（具体目标I），彻底表征爆炸伤对大脑和视觉系统（视网膜，视神经，视皮层）的功能和结构的影响。由于我们确定了脑出血与严重神经损伤和死亡之间的高度相关性，因此在本提案中，我们将评估我们实验室开发的新型聚合物合成血小板聚集剂的治疗效果，并评估这种方法是否会降低死亡率以及与TBI相关的神经和视觉缺陷（特定目标II）。此外，我们设法产生能够在最大血管损伤部位靶向释放类固醇的基于聚合物的合成血小板，我们将研究这种新的治疗方法是否会减少TBI损伤的大脑和眼睛中的视觉和神经异常（特定目标III）。 这一建议的成功结果可能会显着提高我们的理解与创伤性爆炸伤相关的视觉系统和脑异常。此外，开发基于合成聚合物的血小板，其可以被工程化用于在具有最突出的血管损伤的CNS部位靶向释放不同的药物，这可能是预防与暴露于冲击伤相关的死亡和长期神经问题的有效策略。 本研究中提出的实验与受伤战士的治疗和康复具有高度相关性，并且与退伍军人管理局和国防部目前在对受爆炸引起的创伤性脑损伤影响的患者进行高级护理方面的首要任务一致。

DESCRIPTION (provided by applicant): Abstract Traumatic brain injuries (TBI) and organ polytraumas caused by explosive blast have been identified as the most frequent cause of death and injury in current military engagements in Iraq and Afghanistan, with up to 20% of veterans returning to the United States having experienced some form of TBI. The explosive blast exposure in the battlefield conditions can cause peracute and acute symptoms of severe neurological dysfunction due to the blast induced shear damage to neurons and brain vasculature. Exposure to the blast wave can result in an immediate development of the shock and frequently results in the rapid death or chronic incapacitation, which dictates the need for more aggressive development of novel diagnostic and treatment modalities for TBI. We developed an experimental model of blast-induced TBI in mice and demonstrated that experimental mice exposed to blast wave share many features previously reported in human patients such are decreased visual function, abnormal vestibular function and impaired learning capacity. In this proposal we are planning to further expand on our studies and address following specific aims: we will thoroughly characterize effects of blast injury on the function and structure of brain and visual system (retina, optic nerve, visual cortex) by using battery of functional, structural, molecular and behavior based tests (Specific Aim I). Since we identified high correlation between brain hemorrhage and severe neurological damage and death, in this proposal we will evaluate the therapeutic efficacy of novel polymer-based synthetic platelet aggregators developed in our laboratory and evaluate whether this approach will decrease mortality and neurological and visual deficits associated with TBI (Specific Aim II). Furthermore, we managed to produce polymer-based synthetic platelets capable of targeted steroid release at sites of maximal vascular damage and we will investigate whether this novel therapeutic approach will decrease visual and neurological abnormalities in TBI injured brains and eyes (Specific Aim III). The successful outcome of this proposal may significantly improve our understanding of visual system and brain abnormalities associated with traumatic blast injury. Furthermore, development of synthetic polymer based platelets which can be engineered for targeted release of different drugs at the CNS sites with the most prominent vascular damage may be an effective strategy for preventing death and long term neurological problems associated with exposure to the blast injury. The proposed experiments in this study have a high relevance for the treatment and rehabilitation of wounded warriors and are consistent with current top priorities of the Veterans Administration and Department of Defense in terms of advanced care for patients affected by blast-induced traumatic brain injury.