Ocular Sequelae and Intervention in a Rat Model of Blast Overpressure Polytrauma

军事人员经常暴露在爆炸诱发的冲击波(声波爆炸超压， ABO)，强度足以引起多发伤，其中创伤性脑损伤(TBI)是常见的 组件。对于视网膜结构或功能本身的影响，人们知之甚少 由ABO暴露引起的，最初可能是隐蔽的，直到几周后才明显显现 爆炸后的几个月。这个项目的重点是提供一个病因和治疗的理解。 ABO相关的视网膜和视觉系统缺陷以及伴随而来的中枢神经系统和运动系统损害 和功能障碍。先前的研究表明，氧化应激与ABO诱导的心肌梗死的病理生理机制有关 多发性创伤，提示抗氧化剂可能提供了一种有效的治疗干预 受伤。此外，神经保护剂在大鼠模型上显示了干预脑损伤的前景。 使用直接机械冲击大脑(即“侧向液压冲击”(LFP)模型)。在这里， 我们直接比较了我们的大鼠ABO原发冲击伤模型和免费的LFP TBI模型， 并显示了将这两个模型联系在一起的“分子签名”，这表明了 两种情况下观察到的病理改变。使用这两种模型，我们将测试一种新型的血脑-- 屏障通透性多功能抗氧化剂(MFAO(HK-2))和神经保护剂 (苯氧苯甲胺)，单独或联合使用，以限制多发伤的严重程度。目标1将 HK-2和PBZ预防或减轻ABO致多发伤的疗效评价 (视觉、认知和神经运动缺陷，以及中枢神经系统结构异常)。以类似的方式， 目的2评价HK-2和PBZ预防或减轻低密度脂蛋白诱导的疗效 多处创伤。最先进的评估视觉、认知和神经运动功能的方法 作为视网膜和大脑的结构，将与相关的生化、免疫学和 组织学方法论。与现役军人和退伍军人医疗保健问题的相关性：TBI是 伊拉克和阿富汗冲突的标志性伤害(OEF/OIF)。目前，还没有有效的 治疗或预防性干预，以尽量减少或预防ABO引起的多发伤，包括创伤性脑损伤 以及随之而来的视力缺陷。数以千计的现役军事人员受到这样的伤害- 引发反复发作的情况，这为以下方面提出了一个重大的悬而未决的医疗问题 现役军人和退伍军人。PIS和环境：站点1 PI(Fliesler)有35年的使用年限 眼睛/视力研究的生产力记录，包括视网膜退行性变的动物模型和 采用了多种分子/细胞生物学方法。他是视觉研究部的主任 中心和水牛城VAMC的研究职业科学家奖(RCSA)获得者，以及 本系讲座教授/副主任/研究主任。布法罗大学眼科博士 (UB)。他有ABO大鼠模型和HK-2内部模型。UB协作者(Poulsen)拥有LFP模型 在他的实验室建立，使用大鼠LFP脑损伤模型已有15年，并研究了 使用这种模型的神经保护剂。他是翻译神经科学教授，也是 在神经外科，在功能行为和认知方面都有丰富的经验 相对于大鼠颅脑损伤模型的评估。网站2派(帕杜)是亚特兰大RCSA的获奖者 VAMC，Assoc.亚特兰大退伍军人康复研究与发展卓越中心科学项目主任，以及 佐治亚理工学院生物医学工程教授，有25年的工作经验 在眼睛/视力研究中，特别是涉及电生理和行为诊断方法的时候。 PI具有已建立的和持续的协作关系，并拥有最好的资源和 确保该项目成功实施的支持性环境。

Military personnel are frequently exposed to blast-induced shock waves (acoustic blast overpressure, ABO), with intensities sufficient to cause polytrauma, of which traumatic brain injury (TBI) is a common component. Relatively little is known about the structural or functional effects on the retina per se induced by ABO exposure, which initially may be occult and not manifest significantly until weeks to months post-blast. This project focuses on providing an understanding of the etiology and treatment o f ABO-associated retinal and visual system defects, as well as attendant CNS and motor system damage and dysfunction. Prior studies have implicated oxidative stress in the pathophysiology of ABO-induced polytrauma, suggesting that antioxidants may provide an effective therapeutic intervention against such injury. In addition, neuroprotective agents have shown promise for intervening in TBI, using a rat model employing direct mechanical impact to the brain (i.e., the “lateral fluid percussion” (LFP) model). Herein, we directly compare our rat ABO model of primary blast injury against the complimentary LFP TBI model, and show “molecular signature” linking the two models, suggesting common underlying mechanisms for the observed pathologies in both. Using both models, we will test the efficacy of a novel, blood-brain- barrier permeable multifunctional antioxidant (MFAO (“HK-2”)) and a neuroprotectant (phenoxybenzamine (“PBZ”)), alone and in combination, to limit the severity of polytrauma. AIM 1 will evaluate the therapeutic efficacy of HK-2 and PBZ in preventing or attenuating ABO-induced polytrauma (visual, cognitive and neuromotor deficits, and CNS structural abnormalities). In an analogous manner, AIM 2 will evaluate the therapeutic efficacy of HK-2 and PBZ in preventing or attenuating LFP-induced polytrauma. State-of-the-art methods for assessing visual, cognitive, and neuromotor function, as well as retina and brain structure, will be employed, along with correlative biochemical, immunological, and histological methodologies. Relevance to Active Military and Veterans' Healthcare Issues: TBI is the signature injury of the conflicts in Iraq and Afghanistan (OEF/OIF). Currently, there are no effective treatments or prophylactic interventions to minimize or prevent ABO-induced polytrauma, including TBI and attendant vision deficits. With thousands of active military personnel being subjected to such injury- provoking conditions on a recurrent basis, this presents a significant unresolved healthcare issue for active military personnel and Veterans. PIs and Environment: The Site 1 PI (Fliesler) has a >35-year record of productivity in eye/vision research, involving animal models of retinal degenerations and employing a diversity of molecular/cell biological methodologies. He is Director of the Vision Research Center and a Research Career Scientist Award (RCSA) recipient at the Buffalo VAMC, and an endowed chair Professor/Vice-Chair/Research Director in the Dept. of Ophthalmology at the University at Buffalo (UB). He has the ABO rat model and HK-2 in-house. A UB collaborator (Poulsen) has the LFP model established in his lab, has utilized the rat LFP TBI model for >15 years, and has investigated multiple neuroprotective agents using this model. He is a Professor of Translational Neuroscience and a member of the Neurosurgery Department, and has extensive experience in both functional behavior and cognitive assessments relative to the rat TBI model. The Site 2 PI (Pardue) is a RCSA recipient at the Atlanta VAMC, Assoc. Director of Scientific Projects at the Atlanta VA Rehab R&D Center of Excellence, and Professor of Biomedical Engineering at Georgia Institute of Technology, with >25 years of experience in eye/vision research, particularly as involves electrophysiological and behavioral diagnostic methods. The PIs have an established and ongoing collaborative relationship, and have superlative resources and supportive environments to ensure the successful execution of this project.