Understanding the Injury Mechanism of Blast Neurotrauma

描述（由申请人提供）： 在目前的伊拉克和阿富汗战争中，美国军队遭受创伤性脑损伤（TBI）的人数很多，这可能与爆炸暴露的增加直接相关。结论是，在这些战区记录的头部和颈部受伤的比例比以往任何冲突都要高。爆炸物占这些受伤人数的78%，是任何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，爆炸超压风险一直在上升。轻度TBI（mTBI）与头痛、记忆和睡眠障碍有关。这些问题可能会持续存在，并可能延长从合并症中恢复的时间。为了更好地了解冲击波超压对大脑的影响，我们的研究小组开发了一种啮齿动物冲击波神经损伤模型。报告表明，低水平的超压暴露可引起认知和组织学改变，表明中枢神经系统受累。然而，爆炸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确定行为和认知评估，这些评估将定义爆炸神经创伤并预测爆炸暴露后的恢复模式。我们推测，爆炸能量传输到大脑会导致细胞水平的损伤，从而导致可测量的行为和认知变化。这项初步研究将提供一个更好的表征我们的啮齿动物冲击神经创伤模型，并将有助于澄清 爆炸暴露损伤机制。我们将研究哪些细胞级联和神经认知/行为变化是爆炸性神经创伤损伤的指标。我们的具体目标是（1）完善一系列行为和神经认知损害测试，以密切模拟暴露于爆炸性神经创伤的军事人员中观察到的损害，以及（2）利用组织学方法指导可能导致爆炸性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，我们希望已经确认和进一步发展的实验动物模型的冲击波神经创伤。我们希望证明爆炸相关的神经病理学和神经认知/行为变化之间的关联。朝着一个高度可靠的实验模型，准确地代表退伍军人与爆炸性TBI的临床问题的进展将有助于有效的诊断和治疗制度，目前缺乏和阻碍我们的退伍军人的最大恢复的发展。 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。据报道，大多数被送往医院的爆炸暴露士兵被诊断为创伤性脑损伤，其中相当多的人被确定为轻度创伤性脑损伤。由于所有类型的TBI都可能发展为慢性疾病，因此这项研究 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影响。此外，爆炸诱导的mTBI表现出许多症状，这将扩大临床医生的诊断职责。通过开发适当的动物模型，准确地代表慢性mTBI的人类结果，我们可以进一步设计更有效的治疗药物，以更好地为我们的退伍军人服务。

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.