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

描述（由申请人提供）： 军事人员经常暴露于爆炸超压冲击波，其强度足以引起多发性创伤，即，对神经系统和内脏器官的直接机械损伤。爆炸超压暴露对视网膜本身的主要影响知之甚少，最初可能是隐匿的，直到爆炸后数周至数月才明显显现。该项目的重点是提供一个了解的病因和治疗爆炸超压相关的视网膜变性和视觉缺陷，在这种情况下。使用大鼠模型和一种新的冲击波发生器装置诱导原发性冲击波损伤，我们提供了证据的“分子签名”在神经视网膜和视网膜色素上皮细胞，在这些条件下出现，是已知的生物标志物与氧化应激和神经元变性。最近的相关研究爆炸波引起的损伤强烈牵连氧化应激的病理生理学相关的组织损伤。此外，铁，催化自由基的形成，已牵连在广泛的视网膜变性以及创伤性脑损伤（TBI）。这表明抗氧化剂，包括铁螯合剂和自由基清除剂， 限制这种损害的严重性。本研究的近期目标是阐明冲击波超压暴露后视网膜损伤和功能障碍的分子和细胞基础，以及检测去铁酮的治疗效果（FDA批准的铁螯合剂）和一种新颖的专有螯合剂-自由基清除剂（多功能抗氧化剂，MFAO）在抑制大鼠模型中爆炸诱导的视网膜变性和功能障碍方面的作用。将采用最先进的视觉功能和相关的生物化学，免疫学，形态学和超微结构的方法。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爆炸相关的视力丧失和视觉系统退化。假设冲击波超压暴露将诱导视网膜和视觉系统的功能（第一）和结构（第二）的进行性和不可逆的损伤，这种损伤将通过与氧化应激，细胞死亡和神经胶质增生相关的特定生物标志物的上升而发生，并且这种损伤和生物标志物水平将通过适当的时间抗氧化剂给药而显着减弱。与现役军人和退伍军人医疗保健问题的相关性：目前，没有有效的治疗或预防性干预措施来最大限度地减少或预防爆炸超压引起的视网膜损伤或功能障碍。由于成千上万的现役军人每天都可能遭受这种致伤条件，这对现役军人和退伍军人来说是一个重要但未得到充分解决的临床护理问题。PI和环境：研究中心1 PI（Fliesler）在眼睛/视力研究方面拥有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，并采用多种生物化学，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（一所充满活力的研究密集型大学）眼科系的捐赠讲座教授和副主席，以及布法罗翻译联盟内翻译试点研究项目的联合主任。研究中心2 PI（Pardue）是Atlanta VAMC的研究职业科学家、Atlanta VA Rehab R&D Center of Excellence的科学项目副总监和Emory University的眼科学副教授，在眼睛/视觉研究方面拥有超过20年的经验，特别是涉及电生理和行为诊断方法的经验。PI有一个既定的合作关系，并有最好的资源和支持环境，以确保该项目的成功执行。

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.