Brain swelling 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 and the extracellular space of the brain. The goals of this research proposal include establishing more definitely this critical role of the astrocyte and investigating mechanisms by which this cell achieves net movement of water and solute. A third goal is to determine the relationship between this cell function and the pathogenesis of cytotoxic edema. Cell volume responses of primary cultured astrocytes to altered osmolarity will be studied as a model of astrocyte control of brain water. Techniques developed previously in this laboratory will be refined to permit quantitative measures of water and ion movements during hyper- and hypo-osmotic exposure. The contributions of various ion channels and transport systems to these volume responses will be identified. Finally, we shall study the effects on astrocyte volume regulation of factors which may contribute to the pathogenesis of cytotoxic edema in Reye's Syndrome and cerebral ischemia. We shall correlate these in vitro studies with in vivo states of cerebral edema by quantifying water and ion movements in the brains of animals exposed to those agents which affect astrocyte volume control in vitro. These studies will provide insight into the mechanisms of astrocyte volume control under physiological conditions and the processes important in the genesis and resolution of brain edema in pathologic conditions. Knowledge of these mechanisms will provide testable hypotheses relating to the production and resolution of brain edema in critical clinical states including Reye's Syndrome and cerebral ischemia. In addition, these studies may suggest rational therapies for cytotoxic brain edema.
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