Support is requested to continue a multidisciplinary program that was begun in 1993 under the auspices of a P2O from NINDS. Through the study of a variety of pathological states such as perinataI asphyxia, neonatal stroke and neonatal infection, patterns and mechanisms of ischemic neonatal brain injury will be elucidated. It is the hypothesis of this proposal that the integrity of the blood brain barrier, cerebral perfusion, excitatory amino acid release availability of neurotrophic factors and substrates of intermediary metabolism, are critically important factors in the pathogenesis of neonatal brain injury. Through an integration of human research and basic science research we plan to study the role of these factors in the pathogenesis of neonatal ischemic brain injury. Taking what we observe in the human condition, we will develop new animal models and techniques, as well as use existing animal models and tissue culture paradigms with established methodology to unravel mechanisms. Through continuous in situ monitoring of injury viaMRI/MRS and near infrared spectroscopy(NIRS), we will be better equipped to study these mechanisms and meet our ultimate goal of providing therapies in the nursery for ischemic brain injury. Each project is conceptually interrelated and utilizes the scientific core for a centralized facility for all experimental manipulations. The programs four projects are 1) MRI predictors of outcome after perinatal asphyxia in humans, 2) Fructose bisphosphate in asphyxial brain injury 3) Neurotrophins in neonatal hypoxic-ischemic brain injury and 4) Mediators of ischemic brain injury in neonatal meningitis. Through these varied approaches we will investigate the cellular, molecular and physiological mechanisms of hypoxia/ischemia in the developing nervous system.
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