Support is requested to establish a multidisciplinary research program to investigate the role of ischemia in the generation of neonatal brain injury. Through the study of a variety of pathological states such as neonatal stroke, drug intoxication and 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, the availability of neurotrophic factors and excitotoxin release are critically important factors in the pathogenesis of neonatal brain injury. The focus in each project will be on particular factors that may influence the degree of ischemia. The first two projects involve human subjects. In the first project, cerebral perfusion and blood brain barrier integrity as assessed by perfusion contrast MRI scans will be correlated with regional and extracellular fluid levels of glutamate as measured by magnetic resonance spectroscopy and high performance liquid chromatography in the term asphyxiated neonate. In project 2 another important cause of ischemic brain injury in neonates, in utero exposure to cocaine and its metabolites, will be studied. The neurological syndromes associated with cocaine intoxication and withdrawal will be defined using pharmacological data. The laboratory projects will focus on mechanisms of neuronal survival in the setting of injury caused by asphyxia and infection. In project 3, the role of fructose bisphosphate in ameliorating asphyxial brain injury in beagle pups and neonatal rats will be studied in a preclinical trial. in project 4, the response of NGF and NGF receptors will be investigated in a neonatal rat model of hypoxia-ischemia and the effects of NGF on neuronal survival will be measured in vivo and in vitro after hypoxia ischemia. Project 5 will use a neonatal rat model of Group B streptococcal meningitis to explore the role of hypoxia-ischemia in the setting of central nervous system infection and inflammation. The histopathology will be defined and the additive effects of inflammation and hypoxia will be studied using heat shock protein 72 expression as a marker of ischemic stress both in vivo and in vitro. Administrative and laboratory core components will provide cost-effective shared resources. Thus, the projects provide an interdisciplinary link from animals to humans ranging from in vitro to in vivo models of biochemical, physiological and morphological bases of various types of ischemic brain injury. Understanding the role of ischemia in the development of neonatal brain injury will enable us to design effective therapies and better predict neurologic outcome.
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