IL-1 mediated potentiation of hypoxic neuronal injury

University Of Connecticut Sch Of Med/Dnt, Farmington CT

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Abstract

DESCRIPTION (provided by applicant): Changes in lnterleukin-1beta (IL-1beta) levels and/or signaling have been implicated in the pathogenesis of cerebral ischemia; however, the mechanism(s) by which this cytokine contributes to neuronal injury are unknown. Therefore, the overall goal of the proposed research project is to investigate the cellular and biochemical pathway(s) by which this cytokine contributes to neuronal injury, utilizing an in vitro model, in which the endogenous production of IL-1beta is simulated by exogenous addition of recombinant IL-1beta and neuronal injury induced by oxygen deprivation. Specifically, utilizing cultures isolated from IL-1 receptor type l-deficient mice, the cell type(s) (astrocytes and/or neurons) mediating the ill effects of IL-1 beta will be identified. Additionally, the hypothesis that activation of neuronal metabotropic glutamate receptor 1 alpha (mGluRlalpha) is necessary for IL-1-mediated injury to occur will be tested. Immunoblotting, immunocytochemistry and pharmacological and genetic approaches will be used to test the hypothesis that IL-1 beta signaling leads to an increased functional expression of mGluR1alpha or enhances mGluRIalpha activity via inhibition of astrocytic glutamate uptake.