FAS Death Receptor Activation in Neonatal Brain Injury

描述（由申请人提供）：新生儿脑损伤中经常发生纹状体和丘脑损伤，导致感觉-运动整合异常，导致脑瘫儿童严重的运动、感觉、学习和整合障碍。使用Rice-Vannucci模型的新生儿缺氧缺血性（HI）脑损伤，我们已经表明，神经退行性病变发生在纹状体和丘脑，与初始坏死细胞死亡，其次是神经退行性病变的第二阶段，其中一个频谱的细胞死亡结构，包括坏死，细胞凋亡，并发生凋亡-坏死连续表型。Fas死亡受体是唯一已知的介导坏死和凋亡细胞死亡的受体。我们最近报道，新生儿HI后，丘脑细胞死亡发生与激活的Fas死亡受体途径在体内的多个组件。此外，我们现在发现，在体外培养的丘脑神经元表现出不同的表型比皮层神经元和丘脑神经元高度富集Fas死亡受体。我们的数据表明，Fas死亡受体在发育中的脑深部核团的迟发性神经变性中起重要作用。无论是在体内和体外模型的纹状体/丘脑损伤，我们将测试的假设，Fas死亡受体激活发生作为一个直接后果的缺氧缺血和结果在未成熟的丘脑和纹状体的神经变性。Fas死亡受体的激活改变了促凋亡和抗凋亡的细胞内信号级联，通过多种机制导致细胞死亡：坏死、凋亡和细胞死亡的连续表型。我们将利用免疫组化，电子显微镜，生物化学和分子技术，目的1：确定Fas死亡受体激活的重要性，在脑深部核新生儿HI。目的2：确定病理性Fas死亡受体激活对促生存和促凋亡细胞内Fas信号通路的影响。目标3：确定Fas死亡受体激活的机制，在体外未成熟的丘脑神经元后，HI模拟氧-葡萄糖剥夺。这些研究将首次提供Fas死亡受体介导的窒息性脑损伤的发病机制的详细见解和重要的见解，复杂的生物化学的神经变性在未成熟的大脑，似乎发生沿着一个连续的坏死凋亡。

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.