The purpose of this project is to elucidate the cellular and molecular events which promote recovery following cerebral hypoxia-ischemia in the immature rat. The overall hypothesis is that specific cellular and molecular mechanisms are induced in the brain in response Preliminary studies from our laboratory demonstrate that two such in vivo paradigms which can be studied in the 7-old rat are: 1) short-intermediate intervals of hypoxia-ischemia. The experimented proposed in this research project are designed to investigate three major, interrelated areas of functional activity in the immature brain which may promote cellular survival after hypoxia-ischemia: cerebral nutrient transport, neuroprotective actions of growth factors, and the role of astrocytes in maintaining homeostasis and promoting neuronal survival. To this end, this project will pursue three specific aims: 1) to determine the effect the effect of the duration and severity of the hypoxic-ischemia insult on the nature and time-course of alterations in neural gene and protein expression and the relationship of these changes to tissue damage. These studies will employ in situ hybridization and protein analyses to assess alterations in glucose and monocarboxylate transporter proteins and the neurotrophins, in combination with MR imaging and detailed neuropathological analysis to recreate the temporal and spatial pattern of cellular changes following mild-moderate, relative to severe, ischemia; 2) to determine the mechanisms by which hypoxic preconditioning protects against known to provide significant approach as in Aim 1 in a experimental paradigm of hypoxic preconditioning known to provide significant neuroprotection from a subsequent severe ischemic insult: and 3) to determine the role of astrocytes which became activity within the hypoxic ischemic-hemisphere early in recovery in providing neuroprotection. The experiments will combined combine two in vivo and in vitro approaches to investigate the functional activity of activated astrocytes which may contribute to neuronal survival. The results of these studies will provide important information relative to the cellular and molecular basis of the pathophysiology of hypoxic-ischemic brain damage in the immature animal in conditions commensurate with tissue survival.
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