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

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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.