FAS Death Receptor Activation in Neonatal Brain Injury

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DESCRIPTION (provided by applicant): Injury to the striatum and thalamus occurs frequently in neonatal brain injury and results in abnormalities of sensory-motor integration that contributes to the severe motor, sensory, learning and integrative handicaps suffered by children with cerebral palsy. Using the Rice-Vannucci model of neonatal hypoxic-ischemic (HI) brain injury, we have shown that neurodegeneration occurs in the striatum and thalamus, with initial necrotic cell death followed by a secondary phase of neurodegeneration in which a spectrum of cell death structures including necrosis, apoptosis, and an apoptosis-necrosis continuum phenotypes occurs. Fas death receptor is the only known receptor to mediate both necrotic and apoptotic cell death. We recently reported that, following neonatal HI, thalamic cell death occurs with activation of multiple components of the Fas death receptor pathway in vivo. Additionally, we now find that thalamic neurons grown in vitro exhibit a different phenotype than do cortical neurons and thalamic neurons are highly enriched in Fas death receptor. Our data suggest that Fas death receptor plays an important role in delayed neurodegeneration in the developing deep brain nuclei. With both in vivo and in vitro models of striatal/thalamic injury, we will test the hypothesis that Fas death receptor activation occurs as a direct consequence of hypoxia-ischemia and results in neurodegeneration in the immature thalamus and striatum. Fas death receptor activation alters pro- and anti-apoptosis intracellular signaling cascades resulting in cell death by a variety of mechanisms: necrosis, apoptosis and a continuum phenotype of cell death. We will utilize immunohistochemical, electron microscopy, biochemical, and molecular techniques to Aim 1: Determine the importance of Fas death receptor activation in the deep brain nuclei following neonatal HI. Aim 2: Determine the effect of pathologic Fas death receptor activation on both pro-survival and pro-apoptosis intracellular Fas signaling pathways. Aim 3: Determine the mechanisms of Fas death receptor activation in immature thalamic neurons in vitro following HI as mimicked by oxygen-glucose deprivation. These studies will provide the first detailed insight into the pathogenesis of Fas death receptor mediated asphyxial brain injury and important insights into the complex biochemistry of neurodegeneration in the immature brain that appears to occur along a continuum of necrosis to apoptosis.