The studies outlined in this proposal form a cohesive theme focused on ischemic injury and recovery mechanisms in perinatal hypoxia-ischemia. These projects arose as an outgrowth of the last cycle, but with new and exciting directions for the projects. We will now turn our attention to the long-term repair and recovery mechanisms. Our multi-disciplinary approach is maintained in this renewal with the human research project and three laboratory projects that all inform each other and are supported by two cores. The administrative core provides budgetary oversight, training and data management, while the technology core provides a central facility for both the human and laboratory studies for MR imaging and development as well as a repository for MRI development. In Project 1 White matter injury as predictor of outcome in neonatal brain injury, we plan to focus on the injury to white matter and to correlate the damage in major white matter pathways with neurodevelopmental outcome. We will utilize short echo 3D MR spectroscopic imaging (SEMRSI) to detect changes in metabolites relevant to the injury process, and we also propose to apply high angular resolution diffusion tensor imaging (HARDI) to detect small changes in water diffusion parameters (diffusivity and anisotropy). In Project 2 Role of Vascular Endothelial Growth Factor (VEGF) in recovery after ischemic neonatal brain injury, we will test whether VEGF plays a critical role in long-term recovery after neonatal stroke by promoting angiogenesis and neurogenesis. In Project 3 Effects of polyphenols on neonatal Hypoxia-ischemia (H-l) brain injury, we hypothesize that exposure to polyphenols from pomegranate juice as well as the specific polyphenol, resveratrol, will protect the neonatal brain against the acute effects of H-l. In addition, we hypothesize that delayed injury that occurs in the setting of neonatal H-l including axonal injury and regeneration will also be responsive to polyphenols. In Project 4 Tissue repair in two models of acute neonatal brain injury, we will focus on the repair process in two distinct models of neonatal brain injury - neonatal bacterial meningitis and transient middle cerebral artery occlusion. The two models share common features during the acute phase, such as tissue inflammation and apoptotic neuronal cell death; very little is known about the repair process in these models. These projects are all relevant to human disease as they will bring us closer to therapies for neonatal brain ischemia. RELEVANCE TO PUBLIC HEALTH: Achieving these goals will ultimately result in improved care and outcome in encephalopathic neonates, and potential therapies aimed at the repair process after neonatal ischemic events.