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

爆炸超压多发伤大鼠模型的眼部后遗症及干预

• 批准号: 10361397
• 负责人: Steven J. Fliesler
• 金额: --
• 依托单位: VA WESTERN NEW YORK HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10361397
• 关键词: Acoustics; Affect; Afghanistan; Animal Model; Animals; Antioxidants; Attenuated; Award; Behavior assessment; Behavioral; Biochemical; Biological; Biological Markers; Biomedical Engineering; Blast Injuries; Brain; Buffaloes; CNS degeneration; Cells; Clinical; Cognitive; Cognitive deficits; Companions; Conflict (Psychology); Data; Defect; Development; Diagnostic Procedure; Electrophysiology (science); Electroretinography; Ensure; Environment; Etiology; Exposure to; Eye; Eye Injuries; Functional disorder; Funding; Generations; Goals; Healthcare; Histologic; Human Resources; Immunologics; Inflammation Mediators; Injury; Institutes; Intervention; Iraq; Knowledge; Lateral; Link; Liquid substance; Long-Term Care; Magnetic Resonance Imaging; Mechanics; Methodology; Methods; Military Personnel; Mission; Modeling; Molecular; Molecular Profiling; Motor; Motor Skills; Multiple Trauma; Neural Retina; Neuroprotective Agents; Ophthalmology; Optic Chiasm; Optic Nerve; Optical Coherence Tomography; Oxidative Stress; Pathologic Processes; Pathology; Percussion; Performance; Plant Roots; Population; Productivity; Quality of life; Rattus; Reaction; Recurrence; Reporting; Research; Resources; Retina; Retinal Degeneration; Retinal Pigments; Risk; Rotarod Performance Test; Scientist; Severities; Shock; Site; Structural defect; Structure; Structure of retinal pigment epithelium; System; TBI treatment; Technology; Testing; Therapeutic Intervention; Time; TimeLine; Tissues; Traumatic Brain Injury; Treatment Efficacy; United States Department of Veterans Affairs; Universities; Vision; Vision research; Visual; Visual Cortex; Visual Pathways; Visual impairment; Visual system structure; War; base; blood-brain barrier permeabilization; career; cognitive skill; cognitive testing; cohort; comparative; effective therapy; efficacy testing; efficacy validation; experience; experimental study; member; military veteran; motor deficit; neuromuscular system; neuropathology; neuroprotection; neurosurgery; novel; pre-clinical; preclinical study; preservation; prevent; preventive intervention; professor; prophylactic; psychologic; research and development; response; retinal damage; sex; supportive environment; therapeutic evaluation; therapeutically effective; translational neuroscience

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.

军事人员经常暴露于爆炸引起的冲击波（声学爆炸过压， ABO），具有足以引起多发性的强度，其中创伤性脑损伤（TBI）是一种常见 成分。关于视网膜本身的结构或功能影响相对鲜为人知 由ABO暴露引起的，最初可能是神秘的，直到几周才能显着表现 爆破后月。该项目着重于提供对病因和治疗的理解 与ABO相关的视网膜和视觉系统缺陷以及随之而来的CNS和运动系统损坏 和功能障碍。先前的研究已经在Abo诱导的病理生理学中实现了氧化应激 多龙骨，表明抗氧化剂可以提供有效的治疗干预措施 此外，神经保护剂使用大鼠模型显示出有望介入TBI 对大脑采取直接的机械影响（即“侧流体打击乐”（LFP）模型）。在此处， 我们直接比较了与免费LFP TBI模型的一级爆炸损伤模型的大鼠ABO模型， 并显示“分子签名”，将两个模型连接起来，提出了共同的潜在机制 两者中观察到的病理。使用这两种模型，我们将测试一种新型血脑验的效率 屏障可渗透多功能抗氧化剂（MFAO（“ HK-2”））和神经保护剂 （苯氧基苯甲胺（“ PBZ”）），单独和组合，以限制多发性的严重程度。目标1意志 评估HK-2和PBZ在预防或衰减ABO诱导的多发性多发性的治疗效率 （视觉，认知和神经运动缺陷，以及中枢神经系统的结构异常）。以类似的方式 AIM 2将评估HK-2和PBZ预防或衰减LFP诱导的治疗效率 多毛。评估视觉，认知和神经运动功能的最新方法 作为视网膜和大脑结构，将被录用，以及相关的生化，免疫学和 组织学方法。与活跃的军事和退伍军人的医疗保健问题有关：TBI是 伊拉克和阿富汗冲突的签名伤害（OEF/OIF）。目前，没有效力 治疗或预防性干预措施，以最大程度地减少或预防ABO诱导的多发性疗法，包括TBI 随之而来的愿景定义。成千上万的活跃军事人员受到这种伤害 - 反复发动条件，这给出了一个重大的未解决的医疗保健问题 活跃的军事人员和退伍军人。 PIS和环境：站点1 PI（佛蝇）的> 35年 眼睛/视力研究中的生产力记录，涉及残余变性的动物模型 采用多种分子/细胞生物学方法。他是视觉研究的主任 中心和研究职业科学家奖（RCSA）获得了布法罗VAMC的获得者， 布法罗大学眼科部主席/副主席/副主席/研究主任 （ub）。他拥有ABO Rat Model和HK-2内部。 UB合作者（Poulsen）具有LFP模型 在他的实验室中建立的，已经使用了大鼠LFP TBI模型> 15年，并研究了多个 使用此模型的神经保护剂。他是转化神经科学的教授，成员 神经外科部门的功能行为和认知方面的经验丰富 相对于大鼠TBI模型的评估。站点2 PI（PARDUE）是亚特兰大的RCSA接收者 VAMC，协会。亚特兰大弗吉尼亚州康复研发卓越中心的科学项目主管， 佐治亚理工学院生物医学工程教授，拥有> 25年的经验 在眼睛/视力研究中，特别是涉及电生理和行为诊断方法。 PI具有建立且持续的合作关系，并具有最高级的资源和 支持环境，以确保成功执行该项目。