Traumatic brain injuries (TBI) and organ polytraumas caused by explosive blast have been identified as the most frequent cause of death and injury in current military engagements in Iraq and Afghanistan, with up to 20% of veterans returning to the United States having experienced some form of TBI. The explosive blast exposure in the battlefield conditions can cause peracute and acute symptoms of severe neurological dysfunction due to the blast induced shear damage to neurons and brain vasculature. Exposure to the blast wave can result in an immediate development of the shock and frequently results in the rapid death or chronic incapacitation, which dictates the need for more aggressive development of novel diagnostic and treatment modalities for TBI. We developed an experimental model of blast-induced TBI in mice and demonstrated that experimental mice exposed to blast wave share many features previously reported in human patients such are decreased visual function, abnormal vestibular function and impaired learning capacity. In this proposal we are planning to further expand on our studies and address following specific aims: we will thoroughly characterize effects of blast injury on the function and structure of brain and visual system (retina, optic nerve, visual cortex) by using battery of functional, structural, molecular and behavior based tests (Specific Aim I). Since we identified high correlation between brain hemorrhage and severe neurological damage and death, in this proposal we will evaluate the therapeutic efficacy of novel polymer-based synthetic platelet aggregators developed in our laboratory and evaluate whether this approach will decrease mortality and neurological and visual deficits associated with TBI (Specific Aim II). Furthermore, we managed to produce polymer-based synthetic platelets capable of targeted steroid release at sites of maximal vascular damage and we will investigate whether this novel therapeutic approach will decrease visual and neurological abnormalities in TBI injured brains and eyes (Specific Aim III). The successful outcome of this proposal may significantly improve our understanding of visual system and brain abnormalities associated with traumatic blast injury. Furthermore, development of synthetic polymer based platelets which can be engineered for targeted release of different drugs at the CNS sites with the most prominent vascular damage may be an effective strategy for preventing death and long term neurological problems associated with exposure to the blast injury. The proposed experiments in this study have a high relevance for the treatment and rehabilitation of wounded warriors and are consistent with current top priorities of the Veterans Administration and Department of Defense in terms of advanced care for patients affected by blast-induced traumatic brain injury.
Traumatic brain injuries (TBI) and organ polytraumas caused by explosive blast have been identified as the most frequent cause of death and injury in current military engagements in Iraq and Afghanistan, with up to 20% of veterans returning to the United States having experienced some form of TBI. The explosive blast exposure in the battlefield conditions can cause severe neurological dysfunction and vision loss as a result of the blast induced brain hemorrhages and diffuse neuronal damage. The overall research objectives in this proposal are to thoroughly characterize effects of blast injury on the function of brain and visual system, and evaluate the efficacy of novel polymer-based synthetic platelet aggregators administration on reduction of blast-induced hemorrhage, neurological deficits and death. The proposed experiments have a high relevance for the treatment and rehabilitation of wounded warriors and are consistent with current top priorities of the Veterans Administration in terms of advanced care for blast-induced TBI.
|Dutca, Laura M; Stasheff, Steven F; Hedberg-Buenz, Adam et al. (2014) Early detection of subclinical visual damage after blast-mediated TBI enables prevention of chronic visual deficit by treatment with P7C3-S243. Invest Ophthalmol Vis Sci 55:8330-41|
|Yin, Terry C; Britt, Jeremiah K; De Jesús-Cortés, Héctor et al. (2014) P7C3 neuroprotective chemicals block axonal degeneration and preserve function after traumatic brain injury. Cell Rep 8:1731-1740|