Understanding the Injury Mechanism of Blast Neurotrauma

描述(由申请人提供)： 美军在当前的伊拉克和阿富汗战争中遭受创伤性脑损伤(TBI)的人数之多，可能与爆炸暴露的增加有直接关系。结论是，这些剧院记录的头部和颈部受伤的比例比以往任何一次冲突都要大。在这些伤亡中，爆炸物占78%，是所有大规模冲突中报告的最高比例。将轻度创伤性脑损伤与 因此，爆炸超压暴露一直在上升。轻度脑外伤(MTBI)与头痛、记忆和睡眠障碍有关。这些问题可能会持续存在，并可能延长从共病状态中复苏的时间。为了更好地了解冲击波超压对大脑的影响，我们团队开发了一种冲击波神经创伤的啮齿动物模型。报告表明，低水平的超压暴露可导致认知和组织学改变，表明中枢神经系统受累。然而，冲击伤后神经生物学和神经心理学之间的关系尚不清楚，基础科学家和神经心理学家之间缺乏合作，以及反映人类结果的动物模型的缺乏阻碍了进展。因此，我们的生物工程师、神经科学家和神经心理学家团队的长期目标是识别行为和认知评估，这些评估将定义冲击波神经创伤并预测爆炸暴露后的恢复模式。我们假设冲击波能量传递到大脑会在细胞水平上造成损害，从而导致可测量的行为和认知变化。这项初步研究将为我们的啮齿动物冲击性神经创伤模型提供更好的表征，并将有助于澄清 冲击波暴露的损伤机制。我们将调查哪些细胞级联和神经认知/行为变化是冲击性神经创伤的指标。我们的具体目标是(1)改进一系列行为和神经认知障碍测试，以接近模拟军事人员在冲击波神经创伤中观察到的损害，并(2)利用组织学方法指导可能导致冲击波神经创伤脑细胞损伤的细胞/分子机制的研究。在这项初步研究的结论中，我们希望确认并进一步发展一种冲击性神经创伤的实验动物模型。我们希望证明与冲击波相关的神经病理和神经认知/行为改变之间的联系。在建立高度可靠的实验模型方面取得进展，准确反映退伍军人BLT脑损伤的临床问题，将有助于开发目前缺乏的、阻碍退伍军人最大限度康复的有效诊断和治疗方案。 公共卫生相关性： 在沃尔特里德陆军医疗中心看到的军事人员中，闭合性头部受伤的人数超过了穿透伤的人数。据报道，入院的大多数遭受爆炸的士兵都被诊断为脑外伤，其中相当多的人被确认为轻度脑外伤。由于所有类型的创伤性脑损伤都可以发展为慢性病，本研究 将对我们的退伍军人和为他们服务所需的医疗保健产生巨大的影响。此外，冲击波诱导的mTBI表现为许多症状，这将扩大临床医生的诊断职责。通过开发准确代表慢性mTBI人类结局的适当动物模型，我们可以进步到设计更有效的治疗剂，更好地为退伍军人服务。

DESCRIPTION (provided by applicant): The high number of US military forces suffering from traumatic brain injury (TBI) in the current wars in Iraq and Afghanistan can be directly related to an increase in blast exposures. It has been concluded that a greater proportion of head and neck injuries were documented in these theaters than in any previous conflict. Explosives accounted for 78% of these injuries, the highest proportion reported for any large scale conflict. The number of reports linking mild TBI to blast overpressure exposure has been rising as a result. Mild TBI (mTBI) is associated with headaches, and memory and sleep disturbances. These problems may persist and can prolong recovery from co-morbid conditions. To better understand the effects of blast overpressure on the brain, our group has developed a rodent model of blast neurotrauma. Reports indicate that low levels of overpressure exposure can induce cognitive and histological alterations, demonstrating central nervous system involvement. However, the relationship between neurobiology and neuropsychology after blast injury is unclear and progress has been hampered by the lack of collaboration between basic scientists and neuropsychologists and of animal models that reflect human outcomes. Thus, the long range objective of our team of bioengineers, neuroscientists and neuropsychologists is to identify behavioral and cognitive assessments that will define blast neurotrauma and predict recovery patterns after blast exposure. We hypothesize that blast energy transmission to the brain causes damage at the cellular level which results in measureable behavioral and cognitive changes. This pilot study will provide a better characterization our rodent blast neurotrauma model and will help clarify the injury mechanism from blast exposure. We will investigate which cellular cascades and neurocognitive/behavioral changes are indicators for blast neurotrauma injury. Our Specific Aims are to (1) refine a series of behavioral and neurocognitive impairment tests to closely model impairment observed in military personnel exposed to blast neurotrauma, and to (2) utilize histological methods to guide investigation of cellular/molecular mechanisms likely to underlie brain cellular damage from blast neurotrauma. At the conclusion of this pilot study, we expect to have confirmed and further developed an experimental animal model of blast neurotrauma. We expect to demonstrate an association between blast-related neuropathology and neurocognitive/behavioral changes. Progress toward a highly reliable experimental model that accurately represents the clinical problems of Veterans with blast TBI will aid in the development of effective diagnostic and treatment regimes that are currently lacking and impeding maximal recovery of our Veterans. PUBLIC HEALTH RELEVANCE: Closed head injuries are out-numbering penetrating injuries among military personnel seen at the Walter Reed Army Medical Center. It has been reported that a majority of blast exposed soldiers admitted to the hospital had been given a diagnosis of TBI, with a significant number identified as mild TBI. Since all classes of TBI can develop into chronic conditions, this research will have an enormous impact on our Veterans and the health care needed to serve them. Furthermore, blast-induced mTBI manifests itself by presenting numerous symptoms, which will expand the diagnostic duties of the clinician. By developing appropriate animal models that accurately represent the human outcomes of chronic mTBI, we can progress to design more effective therapeutic agents to better serve our Veterans.