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: 10735867
• 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/10735867
• 关键词: Acoustics; Affect; Afghanistan; Age; Animal Model; Animals; Antioxidants; Award; Behavior assessment; Behavioral; Biochemical; Biological; Biological Markers; Biomedical Engineering; Blast Injuries; Brain; CNS degeneration; Cells; Cognitive; Cognitive deficits; Companions; Data; Defect; Development; Diagnostic Procedure; Electrophysiology (science); Electroretinography; Endowment; Ensure; Environment; Etiology; Exposure to; Eye; Eye Injuries; Functional disorder; Funding; Generations; Goals; Healthcare; Histologic; Human Resources; Immunologics; Inflammation Mediators; Injury; 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; Penetration; Percussion; Performance; Population; Productivity; Quality of life; Rattus; Reaction; Recurrence; Reporting; Research; Resources; Retina; Retinal Degeneration; Risk; Rotarod Performance Test; Scientist; Severities; Shock; Site; Structural defect; Structure; Structure of retinal pigment epithelium; System; Technology; Testing; Therapeutic Intervention; Time; Tissues; Traumatic Brain Injury; Treatment Efficacy; United States Department of Veterans Affairs; Universities; Veterans; Vision; Vision research; Visual; Visual Cortex; Visual Pathways; Visual System; Visual impairment; War; blood-brain barrier permeabilization; care burden; career; clinical translation; cognitive skill; cognitive testing; cohort; comparative; decubitus ulcer; 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; pressure; prevent; preventive intervention; professor; prophylactic; psychologic; research and development; response; retinal damage; sex; supportive environment; therapeutic evaluation; therapeutically effective; timeline; 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.

军事人员经常受到爆炸引起的冲击波（声爆超压， ABO），强度足以引起多发性创伤，其中创伤性脑损伤（TBI）是常见的 成分对视网膜本身的结构或功能影响知之甚少 由ABO暴露诱导，最初可能是隐匿性的，直到数周才明显表现出来， 几个月后爆炸。该项目的重点是提供一个了解的病因和治疗的f ABO相关的视网膜和视觉系统缺陷，以及伴随的CNS和运动系统损伤 和功能障碍。先前的研究表明，氧化应激与ABO诱导的卵巢癌的病理生理学有关。 多发性创伤，这表明抗氧化剂可以提供有效的治疗干预， 损伤此外，使用大鼠模型，神经保护剂已显示出干预TBI的前景 采用对大脑的直接机械冲击（即，“横向流体冲击”（LFP）模型）。在此， 我们直接比较了我们的原发性冲击伤的大鼠ABO模型与补充的LFP TBI模型， 并显示出连接这两种模型的“分子特征”，表明了共同的潜在机制， 两者的病理学特征。使用这两种模型，我们将测试一种新的血脑- 屏障渗透性多功能抗氧化剂（MFAO（“HK-2”））和神经保护剂 （苯苄明（“PBZ”）），以限制多发性创伤的严重性。AIM 1将 评价HK-2和PBZ预防或减轻ABO致多发伤的疗效 （视觉、认知和神经运动缺陷，以及CNS结构异常）。以类似的方式， 目的2评价HK-2和PBZ在预防或减轻LFP诱导的肝细胞凋亡中的疗效。 多发伤评估视觉、认知和神经运动功能的最先进方法，以及 作为视网膜和脑结构，将被采用，沿着相关的生化，免疫， 组织学方法学。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，没有有效的 治疗或预防性干预，以尽量减少或预防ABO诱导的多发性创伤，包括TBI 以及随之而来的视力缺陷。数以千计的现役军人受到这样的伤害- 反复引发疾病，这是一个重大的未解决的医疗保健问题， 现役军人和退伍军人。PI和环境：研究中心1 PI（Fliesler）具有>35年的 眼睛/视力研究的生产率记录，涉及视网膜变性的动物模型， 采用多种分子/细胞生物学方法。他是视觉研究中心主任 中心和研究职业科学家奖（RCSA）在布法罗VAMC收件人，并赋予 系主任教授/副系主任/研究主任布法罗大学的眼科主任 （UB）。他有ABO大鼠模型和HK-2内部。UB合作者（Poulsen）拥有LFP模型 在他的实验室中建立的，已经使用大鼠LFP TBI模型超过15年，并且已经研究了多个 神经保护剂使用该模型。他是转化神经科学教授， 神经外科的，并具有丰富的经验，在功能行为和认知 相对于大鼠TBI模型的评估。研究中心2 PI（Pardue）是亚特兰大的RCSA接受者 VAMC，亚特兰大VA康复卓越研发中心科学项目副主任， 格鲁吉亚理工学院生物医学工程教授，拥有超过25年的经验 眼睛/视觉研究，特别是涉及电生理和行为诊断方法。 PI有一个既定的和持续的合作关系，并拥有最高级的资源， 支持环境，以确保该项目的成功执行。

项目成果

3,3'-({4-[(4,5-Di-cyano-1H-imidazol-2-yl)diazen-yl]phen-yl}imino)-dipropionic acid.

• DOI: 10.1107/s1600536813011185
• 发表时间: 2013-05-01
• 期刊: Acta crystallographica. Section E, Structure reports online
• 作者: Centore R;Piccialli V;Tuzi A
• 通讯作者: Tuzi A