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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Hicks, Ramona R
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University of California San Francisco
Schools of Medicine
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United States
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Semple, Bridgette D; O'Brien, Terence J; Gimlin, Kayleen et al. (2017) Interleukin-1 Receptor in Seizure Susceptibility after Traumatic Injury to the Pediatric Brain. J Neurosci 37:7864-7877
Semple, Bridgette D; Carlson, Jaclyn; Noble-Haeusslein, Linda J (2016) Pediatric Rodent Models of Traumatic Brain Injury. Methods Mol Biol 1462:325-43
Ryan, Nicholas P; Catroppa, Cathy; Godfrey, Celia et al. (2016) Social dysfunction after pediatric traumatic brain injury: A translational perspective. Neurosci Biobehav Rev 64:196-214
Semple, Bridgette D; Sadjadi, Raha; Carlson, Jaclyn et al. (2016) Long-Term Anesthetic-Dependent Hypoactivity after Repetitive Mild Traumatic Brain Injuries in Adolescent Mice. Dev Neurosci 38:220-238
Semple, Bridgette D; Trivedi, Alpa; Gimlin, Kayleen et al. (2015) Neutrophil elastase mediates acute pathogenesis and is a determinant of long-term behavioral recovery after traumatic injury to the immature brain. Neurobiol Dis 74:263-80
Semple, Bridgette D; Noble-Haeusslein, Linda J; Gooyit, Major et al. (2015) Early Gelatinase Activity Is Not a Determinant of Long-Term Recovery after Traumatic Brain Injury in the Immature Mouse. PLoS One 10:e0143386
Bondi, Corina O; Semple, Bridgette D; Noble-Haeusslein, Linda J et al. (2015) Found in translation: Understanding the biology and behavior of experimental traumatic brain injury. Neurosci Biobehav Rev 58:123-46
Semple, Bridgette D; Noble-Haeusslein, Linda J; Jun Kwon, Yong et al. (2014) Sociosexual and communication deficits after traumatic injury to the developing murine brain. PLoS One 9:e103386
Chen, Chien-Yi; Noble-Haeusslein, Linda J; Ferriero, Donna et al. (2013) Traumatic injury to the immature frontal lobe: a new murine model of long-term motor impairment in the absence of psychosocial or cognitive deficits. Dev Neurosci 35:474-90
Lapchak, Paul A; Zhang, John H; Noble-Haeusslein, Linda J (2013) RIGOR guidelines: escalating STAIR and STEPS for effective translational research. Transl Stroke Res 4:279-85

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