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: 8819205
• 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 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8819205
• 关键词: Address; Adult; Affect; Animal Model; Animals; Antioxidants; Attenuated; Behavioral; Biochemical; Biochemical Markers; Biological; Biological Assay; Biological Markers; Biological Preservation; Blast Cell; Blast Injuries; Blindness; Brain; Buffaloes; Cell Death; Cells; Chelating Agents; Control Animal; Data; Development; Devices; Diagnostic Procedure; Ear; Electron Microscopy; Electroretinography; Ensure; Environment; Etiology; Explosion; Exposure to; Eye; Eye Injuries; FDA approved; Free Radical Formation; Free Radical Scavenging; Free Radicals; Functional disorder; Genetic; Gliosis; Goals; Healthcare; Histology; Human Resources; Immunohistochemistry; Injury; Intervention; Iron; Long-Term Care; Mechanics; Methodology; Methods; Military Personnel; Mission; Modeling; Molecular; Molecular Profiling; Nerve Degeneration; Nervous system structure; Neural Retina; Ophthalmology; Optic Chiasm; Optic Nerve; Optical Coherence Tomography; Oral Administration; Organ; Oxidative Stress; Penetration; Performance; Pilot Projects; Prevention; Productivity; Quality of life; Rattus; Reporting; Research; Resources; Retina; Retinal; Retinal Degeneration; Risk; Scientist; Severities; Shock; Site; Structure; Structure of retinal pigment epithelium; Testing; Time; Tissues; Trauma; Traumatic Brain Injury; Treatment Efficacy; Universities; Veterans; Vision; Vision research; Visual; Visual Cortex; Visual Pathways; Visual impairment; Visual system structure; War; Work; base; career; clinical care; collaborative environment; combat; cost; effective therapy; efficacy testing; experience; follow-up; innovation; insight; male; mild traumatic brain injury; morphometry; novel; pre-clinical; preclinical study; pressure; prevent; professor; programs; prophylactic; psychologic; public health relevance; research and development; retinal damage; soft tissue

DESCRIPTION (provided by applicant): Military personnel are frequently exposed to blast overpressure shock waves, with intensities sufficient to cause polytrauma, i.e., direct mechanical injury to the nervous system and internal organs. Little is known about the primary effects on the retina per se induced by blast overpressure 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 of blast overpressure-associated retinal degeneration and visual deficits under such conditions. Using a rat model and a novel blast generator device to induce primary blast injury, we provide evidence for "molecular signatures" in the neural retina and retinal pigment epithelium that arise under these conditions and that are known biomarkers associated with oxidative stress and neuronal degeneration. Recent related studies of blast wave-induced injuries strongly implicate oxidative stress in the pathophysiology of the associated tissue damage. In addition, iron, which catalyzes free radical formation, has been implicated in a wide range of retinal degenerations as well as in traumatic brain injury (TBI). This suggests the potential therapeutic efficacy of antioxidants, including iron chelators and radical scavengers, to limit the severity of such damage. The immediate goals of the proposed work are (Aim 1) to elucidate the molecular and cellular basis of retinal damage and dysfunction following blast overpressure exposure, and (Aim 2) to test the therapeutic efficacy of deferiprone (an FDA-approved iron chelator) and a novel, proprietary chelator-radical scavenger (multifunctional antioxidant, MFAO) with regard to suppressing blast-induced retinal degeneration and dysfunction in the rat model. State-of-the-art visual function and correlative biochemical, immunological, morphological and ultrastructural methodologies will be employed. The long-term goal is to develop effective mechanism-based strategies for minimizing or preventing blast-associated vision loss and visual system degeneration. The hypothesis is that blast overpressure exposure will induce progressive and irreversible damage to the function (first) and structure (secondarily) of the retina and visual system, that such damage will be preceded by a rise in specific biomarkers associated with oxidative stress, cell death, and gliosis, and tha this damage and biomarker levels will be markedly attenuated by appropriately timed antioxidant administration. Relevance to Active Military and Veterans' Healthcare Issues: Currently, there are no effective treatments or prophylactic interventions to minimize or prevent blast overpressure-induced retinal injury or dysfunction. With thousands of active military personnel potentially being subjected to such injury- provoking conditions daily, this presents a significant, yet under-addressed, clinical care issue for active military personnel and Veterans. PIs and Environment: The Site 1 PI (Fliesler) has a 35-yr record of productivity in eye/vision research, involving genetic and induced animal models of retinal degenerations and employing a diversity of biochemical, molecular and cell biological methodologies. He is Director of the Vision Research Center at the Buffalo VAMC, and also is an endowed chair Professor and Vice-Chair of the Dept of Ophthalmology at SUNY-Buffalo (a vigorous, research-intensive university) and Co-Director of the Translational Pilot Studies Program within the Buffalo Translational Consortium. The Site 2 PI (Pardue) is a Research Career Scientist at the Atlanta VAMC, Assoc. Director of Scientific Projects at the Atlanta VA Rehab R&D Center of Excellence, and Assoc. Professor of Ophthalmology at Emory University, with >20 years of experience in eye/vision research, particularly as involves electrophysiological and behavioral diagnostic methods. The PIs have an established collaborative relationship, and have superlative resources and supportive environments to ensure the successful execution of this project.

描述（由申请人提供）： 军事人员经常暴露于爆炸超压冲击波下，其强度足以造成多发伤，即对神经系统和内脏器官的直接机械损伤。人们对爆炸超压暴露对视网膜本身的主要影响知之甚少，这种影响最初可能是隐秘的，直到爆炸后数周至数月才显着显现。该项目的重点是了解这种情况下与爆炸超压相关的视网膜变性和视力缺陷的病因和治疗。使用大鼠模型和新型爆炸发生器装置来诱导原发性爆炸损伤，我们为在这些条件下出现的神经视网膜和视网膜色素上皮中的“分子特征”提供了证据，这些特征是与氧化应激和神经元变性相关的已知生物标志物。最近对爆炸波引起的损伤的相关研究强烈表明氧化应激与相关组织损伤的病理生理学有关。此外，铁可以催化自由基的形成，它与多种视网膜变性以及创伤性脑损伤（TBI）有关。这表明抗氧化剂（包括铁螯合剂和自由基清除剂）的潜在治疗功效 限制此类损害的严重程度。拟议工作的直接目标是（目标 1）阐明爆炸超压暴露后视网膜损伤和功能障碍的分子和细胞基础，以及（目标 2）测试去铁酮（FDA 批准的铁螯合剂）和新型专有螯合剂自由基清除剂（多功能抗氧化剂，MFAO）的治疗功效 抑制大鼠模型中爆炸引起的视网膜变性和功能障碍。将采用最先进的视觉功能和相关的生化、免疫学、形态学和超微结构方法。长期目标是开发有效的基于机制的策略，以最大限度地减少或预防与爆炸相关的视力丧失和视觉系统退化。假设爆炸超压暴露将对视网膜和视觉系统的功能（首先）和结构（其次）造成进行性和不可逆的损害，在这种损害之前，与氧化应激、细胞死亡和神经胶质增生相关的特定生物标志物会增加，并且这种损害和生物标志物水平将通过适当定时的抗氧化剂施用而显着减弱。与现役军人和退伍军人医疗保健问题的相关性：目前，尚无有效的治疗或预防性干预措施来最大程度地减少或预防冲击波超压引起的视网膜损伤或功能障碍。由于数以千计的现役军人每天都可能遭受此类导致伤害的情况，这对现役军人和退伍军人来说是一个重大但尚未得到解决的临床护理问题。 PI 和环境：Site 1 PI (Fliesler) 在眼睛/视觉研究方面拥有 35 年的生产力记录，涉及视网膜变性的遗传和诱导动物模型，并采用多种生化、分子和细胞生物学方法。他是布法罗 VAMC 视觉研究中心主任，也是纽约州立大学布法罗分校（一所充满活力的研究密集型大学）眼科系的讲座教授和副主席，以及布法罗转化联盟内转化试点研究项目的联合主任。 Site 2 PI (Pardue) 是亚特兰大 VAMC 助理研究员。亚特兰大弗吉尼亚州康复卓越研发中心科学项目总监和副教授。埃默里大学眼科教授，在眼睛/视力研究方面拥有超过 20 年的经验，特别是涉及电生理学和行为诊断方法。 PI们建立了良好的合作关系，并拥有优质的资源和支持环境来确保该项目的成功执行。