FAS Death Receptor Activation in Neonatal Brain Injury

新生儿脑损伤中的 FAS 死亡受体激活

• 批准号: 6780243
• 负责人: FRANCES J NORTHINGTON
• 金额: $ 33.73万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6780243
• 关键词: CD95 molecule; apoptosis; biological signal transduction; brain injury; cell death; cerebral ischemia /hypoxia; corpus striatum; developmental neurobiology; disease /disorder model; electron microscopy; genetically modified animals; immunocytochemistry; intracellular; laboratory mouse; mitochondria; neural degeneration; neuroprotectants; newborn human (0-6 weeks); phenotype; protein quantitation /detection; protein structure function; receptor expression; thalamus; tissue /cell culture; western blottings

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.

描述(申请人提供)：纹状体和丘脑的损伤在新生儿脑损伤中经常发生，并导致感觉-运动整合的异常，导致脑瘫儿童遭受严重的运动、感觉、学习和综合障碍。利用莱斯-万努奇的新生儿缺氧缺血(HI)脑损伤模型，我们发现纹状体和丘脑发生了神经变性，最初是坏死性细胞死亡，随后是第二阶段的神经变性，在此阶段发生了一系列细胞死亡结构，包括坏死、凋亡和凋亡-坏死连续体的表型。Fas死亡受体是目前已知的唯一同时介导细胞坏死性和凋亡性死亡的受体。我们最近报道，在新生儿缺氧缺血性脑病后，体内丘脑细胞死亡伴随着Fas死亡受体通路的多种成分的激活。此外，我们现在发现，在体外培养的丘脑神经元表现出与皮质神经元不同的表型，并且丘脑神经元高度富含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迟发性神经变性中起着重要作用。通过体内和体外的纹状体/丘脑损伤模型，我们将检验Fas死亡受体激活是缺氧缺血的直接结果，并导致未成熟丘脑和纹状体的神经变性的假设。Fas死亡受体的激活通过多种机制改变细胞内促凋亡和抗凋亡的信号级联反应，导致细胞死亡：坏死、凋亡和细胞死亡的连续表型。我们将利用免疫组织化学、电子显微镜、生化和分子技术来研究1：确定新生儿缺氧缺血性脑损伤后脑深部核团Fas死亡受体激活的重要性。目的：探讨病理性Fas死亡受体激活对细胞内促存活和促凋亡Fas信号通路的影响。目的：研究缺氧缺糖对体外培养未成熟丘脑神经元Fas死亡受体激活的影响。这些研究将为Fas死亡受体介导的窒息脑损伤的发病机制提供第一个详细的见解，并为未成熟脑中神经变性的复杂生物化学提供重要的见解，这种复杂的生物化学似乎发生在从坏死到凋亡的连续体中。