Trauma to Developing Brain-Injury and Repair Mechanisms

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DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is the leading cause of disability in children and is associated with significant cognitive deficits. Recent studies indicate that TBI impairs cognitive function to a greater extent in children less than 4 years of age than in older children. Although there has been a considerable effort directed toward understanding the pathobiology of TBI in the adult brain little is known about the consequences of TBI in the child, particularly during the critical period of development. We hypothesize that cognitive impairment after traumatic injury to the immature brain is in part a consequence of cell death resulting from early inflammation. We further hypothesize that this early inflammatory response is exaggerated in the injured, immature brain because of inadequate antioxidant reserves. To test these hypotheses, we will define the contribution of inflammation to early tissue damage after TBI and will determine if increased activity of the antioxidant glutathione peroxidase (GPx) will reduce inflammation and cell injury thereby supporting structural and functional recovery. These studies will rely on a newly developed model of TBI in the immature mouse to address 4 aims. Specific Aim 1 will test the hypothesis that infiltrating leukocytes and microglia/macrophages contribute to cell injury and impair cognitive recovery. Inflammatory blockade and leukocyte depletion will be used in conjunction with flow cytometry, immunocytochemistry and magnetic resonance imaging (MRI) to assess the contribution of inflammation to injury and recovery processes. Specific Aim 2 will test the hypothesis that increased GPx activity in the injured brain reduces oxidative stress/injury, leukocyte recruitment, and barrier disruption. Antioxidant reserve, redox state, and inflammation will be compared in brain injured transgenic mice (Tg) that overexpress GPx with wildtype (Wt) littermates. Specific Aim 3 will test the hypothesis that enriched antioxidant reserves from increased GPx activity attenuates the early inflammatory response through modulation of vascular adhesion molecules and chemokines. We will determine if vascular adhesion molecules and chemokines, defined by Rnase protection assays, and leukocyte infiltration occur preferentially in regions of oxidative stress and if these events are altered in GPx Tg as compared to Wt mice. Specific Aim 4 will test the hypothesis that enriched antioxidant reserves are a determinant of structural and cognitive recovery after TBI. Anatomical and behavioral measures and MRI, will be used to determine if a sustained increase in GPx activity alters cell loss and demyelination, thereby improving cognitive outcome.