Mechanisms of Ischemic Neonatal Brain Injury

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Support is requested to continue a multidisciplinary program that was begun initially as a P20 in response to an RFA from NINDS, and then as a Program Project in 1997. This program will continue to explore in an integrated approach the role of gene expression, progenitor cells, and cell death pathways in the prevention of ischemic injury to the neonatal brain. Through the study of a variety of pathological states such as perinatal asphyxia, focal transient neonatal ischemia and neonatal infection, patterns and mechanisms of ischemic neonatal cell death will be elucidated. With both 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 continue to explore novel pathways of gene expression and cell death, as well as use existing animal models and tissue culture paradigms with established methodology to unravel mechanisms and relate them to neurobehavioral outcomes. Through continuous in situ monitoring of injury via MRI/MRS, we are 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 cores for centralized facilities for experimental manipulations. The four projects of the program are: 1) Magnetic resonance parameters as predictors of outcome in acute neonatal hypoxic-ischemic injury, 2) Role of hypoxia inducible genes in neonatal brain injury, 3) Role of caspase dependent and independent injury and 4) Dentate gyrus injury in neonatal meningitis. The administrative core A will house the statistical support and data management, organize the yearly progress meeting and monthly data panels. Both the MRI Core B and the Neurobehavioral Core C will integrate information gained from the four projects through the administrative core. Through these varied efforts, we will investigate the cellular, molecular and physiological mechanisms of ischemia in the immature nervous system with the goal of developing novel therapies.