Following traumatic brain injury (TBI), the immature rat brain experiences many secondary insults that lead to delayed cell death. Although considerable evidence indicates that mitochondria are primary mediators of ischemic and excitotoxic neural cell death and survival, relatively little is known regarding mitochondrial involvement in adult TBI, and nothing has been reported for models of pediatric TBI. Limited studies of the immature rat brain have demonstrated vulnerability to many known mediators of mitochondrial injury, including elevated intracellular calcium and oxidative stress. Mitochondrial alterations can also trigger the cascade of caspase activities that mediate apoptosis, a process of programmed cell death that appears particularly important in TBI. The working hypothesis for the proposed study is that the response of brain mitochondria to metabolic acidosis, elevated calcium, oxidative stress, and pro-apoptotic proteins plays an integral role in the neurochemical, histologic, and neurologic outcome following pediatric TBI. We will test the following mechanistic hypotheses using a clinically relevant model of pediatric TBI: 1) Mitochondrial injury early after TBI increases the sensitivity of mitochondria to cellular factors that promote apoptotic or necrotic cell death cascades. 2) Cerebral lactic acidosis after TBI promotes cytochrome c release, mediated by mitochondrial swelling due to activation of the membrane permeability transition. 3) Oxidative stress following TBI contributes to mitochondrial dysfunction, cell death and neurologic injury. This study will help define the molecular mechanisms by which mitochondria are injured after TBI in immature animals. This may identify novel targets for neuroprotection following TBI in infants and children. This proposal is intended to provide for the research experience and career development of the applicant, specifically involving the mechanisms of, and therapeutic strategies for, the treatment of acute brain injury. The Departments of Anesthesiology and Pediatrics, and the Brain Injury and Neuroprotection Research Group at the University of Maryland will provide a rich environment for the study of experimental brain injury, and have a strong commitment to fostering meaningful and contemporary research in this field.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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NST-2 Subcommittee (NST)
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University of Maryland Baltimore
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United States
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Robertson, Courtney L; Saraswati, Manda; Scafidi, Susanna et al. (2013) Cerebral glucose metabolism in an immature rat model of pediatric traumatic brain injury. J Neurotrauma 30:2066-72
Robertson, Courtney L; Scafidi, Susanna; McKenna, Mary C et al. (2009) Mitochondrial mechanisms of cell death and neuroprotection in pediatric ischemic and traumatic brain injury. Exp Neurol 218:371-80
Ahn, Edward S; Robertson, Courtney L; Vereczki, Viktoria et al. (2008) Normoxic ventilatory resuscitation following controlled cortical impact reduces peroxynitrite-mediated protein nitration in the hippocampus. J Neurosurg 108:124-31
Casey, Paula A; McKenna, Mary C; Fiskum, Gary et al. (2008) Early and sustained alterations in cerebral metabolism after traumatic brain injury in immature rats. J Neurotrauma 25:603-14
Robertson, Courtney L; Saraswati, Manda; Fiskum, Gary (2007) Mitochondrial dysfunction early after traumatic brain injury in immature rats. J Neurochem 101:1248-57
Robertson, Courtney L; Puskar, April; Hoffman, Gloria E et al. (2006) Physiologic progesterone reduces mitochondrial dysfunction and hippocampal cell loss after traumatic brain injury in female rats. Exp Neurol 197:235-43
Robertson, Courtney L; Soane, Lucian; Siegel, Zachary T et al. (2006) The potential role of mitochondria in pediatric traumatic brain injury. Dev Neurosci 28:432-46
Ahn, Edward S; Robertson, Courtney L; Vereczki, Viktoria et al. (2005) Synthes Award for Resident Research on Brain and Craniofacial Injury: normoxic ventilatory resuscitation after controlled cortical impact reduces peroxynitrite-mediated protein nitration in the hippocampus. Clin Neurosurg 52:348-56
Robertson, Courtney L; Bucci, Cynthia J; Fiskum, Gary (2004) Mitochondrial response to calcium in the developing brain. Brain Res Dev Brain Res 151:141-8
Robertson, Courtney L (2004) Mitochondrial dysfunction contributes to cell death following traumatic brain injury in adult and immature animals. J Bioenerg Biomembr 36:363-8