This exploratory neonatal brain disorders research grant is organized around the central unifying research theme, ischemic brain injury in the neonatal period. The overall program is composed of five interrelated projects, two in clinical neuroscience (Projects 1 and 2) and three in basic neuroscience (Projects 3-5). Project 1 addresses periventricular white matter injury in the premature infant. Considerable data suggest that this injury is caused by disturbances in cerebral blood flow (CBF) and the regulation thereof. However, a direct relationship between such disturbances and the occurrence of these lesions has not been established conclusively in human premature infants, primarily because of methodological deficiencies. We will utilize the new technique of near- infrared spectroscopy (NIRS) to determine whether abnormal reactivity of CBF to blood pressure and to PaCO2 is present in premature infants who develop these white matter lesions. Project 2 addresses the mechanisms of brain injury in mature infants undergoing cardiac surgery with deep hypothermia, cardiopulmonary bypass and circulatory arrest. Considerable data suggest that perioperative events are associated with the occurrence of both neuronal and white matter injury in these infants. We will utilize NIRS and related techniques to study cerebral hemodynamics and oxygen utilization during both the intraoperative and postoperative periods. Project 3 addresses mechanisms of oligodendroglial death studied in cell culture. Preliminary work has defined a maturation- dependent vulnerability of oligodendroglia to glutamate-induced cell death. Delineation of the development aspects of this vulnerability, the mechanisms of the toxicity and the means of prevention will be accomplished. Project 4 addresses the development of oligodendroglia in human brain and the delineation of the specific maturational state of the oligodendroglia particularly affected in periventricular white matter injury. The research will provide major insight into the cellular aspects of PVL. Project 5 addresses in the developing rat model of hypoxic-ischemic brain injury that is particularly relevant to the clinical research of project 2 concerning the infants undergoing cardiac surgery. Combinations of pharmacological agents, e.g., various excitatory amino acid antagonists, novel anti-oxidants, will be studied for their protective effects, with a particular emphasis on combinations that are both effective and likely to be clinically safe. At the end of this exploratory grant our accomplishments should provide major insight for the first time into the relationship of impaired regulation of CBF and the occurrence of periventricular white matter injury in the human premature infant, the mechanisms and timing of disturbances of cerebral hemodynamics and oxygen utilization leading to brain injury in mature infants undergoing cardiac surgery, the mechanisms of glutamate-induced oligodendroglial cell death and the prevention of thereof, the development of oligodendroglia in human brain and the cellular target in PVL, and the determination of an optimal combination of pharmacological agents for utilization in a clinical trial for prevention of brain injury in infants undergoing cardiac surgery. A strong multi-disciplinary core group of clinical and basic scientists will have been established and will form the nucleus for a major center grant on the study of neonatal brain disorders.
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