Brain edema is a critical factor contributing to the mortality and morbidity of individuals with a wide variety of pathologic conditions. The astrocyte is thought to be important in maintaining water volume and electrolyte concentrations in the extracellular space of the brain. The goals of this research project are to understand more definitely the mechanisms by which this cell achieves net movement of water and solute and the relationship between this cell function and the pathogenesis of cytotoxic edema. Cell volume and metabolic responses of astrocytes to conditions of altered osmolarity will be correlated with movements of ions and putative """"""""idiogenic"""""""" amino acid osmolytes. The contributions of various ion channels and transport systems to these volume responses will be defined. The control of intracellular calcium of ion movements induced by antiosmotic exposure will be explored. Finally, the effects of astrocyte volume regulation and solute transport of factors which may contribute to cytotoxic edema in Reye's syndrome, hepatic encephalopathy, and conditions of reduced brain energy metabolic state such as ischemia will be studied. In in vivo studies, the ability of the brain to maintain water homeostasis will be quantified. Blood-brain barrier integrity will be determined and solute movements which contribute to water homeostasis in normal rats and rats subjected to states of cerebral edema will be compared with in vitro studies of astrocytes. These studies will provide a greater understanding of the mechanisms of astrocyte volume regulation under physiologic conditions and the processes responsible for the genesis and resolution of brain edema in pathologic states. Knowledge of these mechanisms will provide new testable hypotheses relating to the development and resolution of brain edema in critical clinical states including Reye's syndrome, hepatic encephalopathy, and ischemia. These studies also may suggest rational therapies for cytotoxic brain edema.
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