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过压力冲击波，其强度足以引起多发性，即直接对神经系统和内部器官进行直接机械损伤。关于爆炸过压暴露引起的对视网膜本身的主要影响，最初可能是神秘的，直到爆破后几周到几个月才显着表现出来。该项目着重于在这种情况下对爆炸过压相关的视网膜变性和视觉缺陷的病因和治疗的理解。使用大鼠模型和新型的爆炸发电机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的“分子特征”提供了证据，并且已知与氧化应激和神经元变性有关的生物标志物。爆炸波诱导的损伤的最新相关研究强烈暗示了相关组织损伤的病理生理学中的氧化应激。此外，催化自由基形成的铁已经与广泛的视网膜变性以及创伤性脑损伤有关（TBI）。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 限制这种损害的严重性。拟议工作的直接目标是（目的1）阐明爆炸过压力暴露后视网膜损伤和功能障碍的分子和细胞基础，（目标2）测试脱脂型（FDA批准的铁螯合剂）的治疗功效，并与新颖的，具有新颖的，专有的固定率（MOLTIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFIFFFINCTANT）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，形态和超微结构方法。长期目标是制定基于机制的有效策略，以最大程度地减少或预防与爆炸相关的视力丧失和视觉系统变性。假设是，爆炸过压暴露将对视网膜和视觉系统的功能（首先）和结构（首先）和结构造成渐进性和不可逆转的损害，此类损害将在与氧化应激，细胞死亡和胶质病相关的特定生物标志物的增加之前，并通过这种损害和生物标志物的降低了，将受到认可的镇定。与活跃的军事和退伍军人的医疗保健问题有关：目前，没有有效的治疗方法或预防性干预措施来最大程度地减少或防止爆炸过压诱导的视网膜损伤或功能障碍。每天有成千上万的活跃军事人员可能会受到这种挑衅的条件，这为活跃的军事人员和退伍军人提出了一个重大但不足的临床护理问题。 PIS和环境：站点1 PI（佛蝇）在眼睛/视力研究中具有35年的生产力记录，涉及视网膜退化的遗传和诱导动物模型，并采用了生化，分子和细胞生物学方法的多样性。他是Buffalo VAMC视觉研究中心的主任，还是Suny-Buffalo（一所充满活力的研究密集于大学）的Ophthalmology部门的主席和副主席，也是Buffalo Transcortation Clansictations Comportium traberations traberational thementational the Translational Pilot研究计划的联合主任。站点2 PI（Pardue）是亚特兰大VAMC的研究职业科学家。亚特兰大VA康复研发卓越中心的科学项目主管和协会。埃默里大学（Emory University）的眼科教授，在眼睛/视力研究方面拥有超过20年的经验，特别是涉及电生理和行为诊断方法。 PI具有建立的协作关系，并具有最高的资源和支持环境，以确保成功执行该项目。