Energy coupled processes use ATP in all prokaryotic and eukaryotic cells. The long-term goal of this project is the physiologic understanding of ATP metabolism (synthesis and utilization) in developing and mature brain. The first hypothesis is that the phosphocreatine (PCr)/creatine kinase (CK)/ATP system, including the mitochondrial CK (MiCK), closely couples ATP synthesis to the variable ATP requirements in mature brain. A second hypothesis is that the PCr/CK/ATP system is central in adaptation of brain ATP metabolism to altered states of energy supply (hypoxia) or energy demand (seizures). A third hypothesis is that at least two PCr/CK/ATP systems exist in brain with the physiology of white matter liked skeletal muscle and gray matter more like smooth muscle. Brain ATP metabolism and PCr/CK/ATP systems will be studied in vivo using 31) nuclear magnetic resonance (NMR) spectroscopy and in vitro using polarographic measures of oxygen consumption in isolated and white and gray matter slices. The NMR studies will measure the CK catalyzed reaction rates and reactant concentrations during hypoxia and seizures. In mice the signals will come from cerebral gray plus white matter. In piglets, the signals will be compared in predominantly gray matter and white matter slices. Three conditions in which brain ATP metabolism is different from mature cerebral cortex will be studied. The first is in mice lacking MiCK in brain. The second condition is in mice which have been fed creatine (Cr) or an analog which either increases or decreases the brain sensitivity to hypoxia. The third condition is ATP metabolism in white and gray matter in metabolically immature and mature piglets on cardiopulmonary bypass. These studies will concentrate on regional effects of hypoxia and ischemia. These studies provide important new approaches to ATP metabolism in regions of the developing and mature brain. The hypotheses are designed to establish physiological principles of brain energy regulation. These principles will be central in understanding the role(s) of energy regualtion in conditions such as normal brain activation and pathogenesis of cellular injury in common clinical conditions such as stroke and status epilepticus. An immediate clinical benefit may arise from further studies of the neuroprotective effects of Cr and Cr analogs in hypoxia. A second clinical benefit will come from studies of mice lacking MiCK, a model for human diseases involving inborn errors of ATP metabolism.
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