Evaluating Causative Effects of Single/Multiple Neurotrauma on Neurodegeneration

 描述（由申请人提供）： 越来越多的美国退伍军人从遭受爆炸暴露和创伤性脑损伤（TBI）的军事企业返回。有一个迫切需要更好地了解长期和衰弱的认知，心理健康和感觉运动能力的障碍。为了进一步复杂的伤害，战斗人员暴露于反复脑震荡可能会发现自己与长期后遗症。这些人中有相当多的人表现出神经退行性疾病和认知能力下降的临床症状。这些人的数量随着当前的战争而增加，对退伍军人事务部构成了重大挑战。缺乏对暴露于战斗相关压力和TBI的退伍军人神经变性病因学的基本神经科学问题的答案。此外，尚不清楚急性损伤如何进展为慢性病理学和病理学。由于大量退伍军人报告患有TBI，研究TBI的长期影响至关重要，因为它与单次或多次创伤后神经系统事件的后遗症有关。这项研究的目标之一是建立一个生物学基础，以确定慢性TBI，这可能有一个显着的影响，从其他神经系统疾病的诊断和鉴别。这种能力可以显着有利于患者的诊断，并将其与其他神经系统疾病区分开来。最终目标是确定各种脑损伤机制是否会促进记忆丧失和神经退行性变的进展。研究设计涉及爆炸性TBI的实验模型。使用军事相关的神经创伤啮齿动物模型，我们期望实现以下具体目标：（1）利用神经认知和行为评估建立单次和多次损伤的纵向效应;（2）鉴定与单次和重复损伤后神经变性相关的慢性生物标志物;（3）使用组织学和分子技术验证神经变性的进展。了解神经创伤的长期后果，并确定从急性向慢性病理转变的机制，将有助于更有效地识别，治疗和优化我们的退伍军人TBI康复策略。我们实验室的最新进展证明了啮齿动物对模拟军事相关TBI（包括多种轻度TBI）的有效性。然而，缺乏长期结果的数据，需要最有效地提供康复策略，以满足损伤和神经退行性疾病进展的个体阶段。理解和测量损伤进展的能力使这项研究与VA使命高度相关。

 DESCRIPTION (provided by applicant): Increasing numbers of US Veterans are returning from military ventures suffering from blast exposure and traumatic brain injury (TBI). There is a critical need for a greater understanding of the long term and debilitating impairments in cognition, psychological health, and sensorimotor abilities. To further complicate the injury, combat personnel exposed to repeated concussions could find themselves with long-term sequelae. A significant number of these individuals are presenting with clinical symptoms of neurodegenerative diseases and cognitive decline. The number of these individuals is increasing with the current war and poses a major challenge for the Department of Veterans Affairs. Answers to fundamental neuroscience questions about the etiology of neurodegeneration in Veterans exposed to combat-related stress and TBI are lacking. Furthermore, it is not known how the acute injury progresses into a chronic pathology and symptomatology. With the large number of Veterans reported to have TBI, it is vital to study the long-term effects of TBI as it relates to the sequelae of neurological events following single or multiple exposures to trauma. One of the goals of this research is to establish a biological basis for identifying chronic TBI which could have a significant effect on diagnosis and differentiation from other neurological conditions. This ability could significantly benefit the patient diagnosis and differentiate it from other neurological conditions. The ultimate goal is to determine if various brain injury mechanisms advance the progression of memory loss and neurodegeneration. The research design involves experimental models of blast TBI. Using military-relevant neurotrauma rodent models, we expect to accomplish the following Specific Aims; (1) to establish the longitudinal effects of both single and multiple injuries in utilizing neurocognitive and behavioral assessments (2) to identify chronic biomarkers which correlate with neurodegeneration following single and repeated injuries and (3) to validate the progression of neurodegeneration using histological and molecular techniques. Understanding the long term consequences of neurotrauma and identifying the mechanisms underlying the transition from acute to chronic pathology will help to more effectively identify, treat and optimie rehabilitative strategies for our Veterans with TBI. Recent advances across our laboratories have demonstrated efficacy of rodents to model military-related TBI including multiple mild TBIs. However, data on long term outcomes are lacking and are required to most effectively provide rehabilitation strategies catering to the individual stage of injury and neurodegeneration progression. The ability to understand and measure injury progression makes this research highly relevant to the VA mission.