FAS Death Receptor Activation in Neonatal Brain Injury

新生儿脑损伤中的 FAS 死亡受体激活

基本信息

批准号：
7217990
负责人：
FRANCES J NORTHINGTON
金额：
$ 32.27万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-03-01 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7217990
关键词：
APAF1 gene Acute Anatomy Apoptosis Apoptotic Attention Attenuated BAX gene Bax protein Binding Biochemical Biochemical Markers Biochemistry Brain Brain Hypoxia-Ischemia Brain Injuries Calpain Caspase Cell Death Cell Nucleus Cerebral Palsy Cessation of life Child Complex Corpus striatum structure Cultured Cells Data Depth Disabled Persons Electron Microscopy Embryo Equilibrium Event Exhibits Fas Signaling Pathway Glucose Goals Harvest Hypoxia In Vitro Infant Injury Investigation Laboratories Learning Mediating Mediator of activation protein Mitochondria Mitochondrial Proteins Modeling Molecular Morbidity - disease rate Morphology Motor Mus Necrosis Neonatal Neonatal Brain Injury Nerve Degeneration Neurons Other Finding Oxygen Pathogenesis Pathologic Pathway interactions Perinatal Phase Phenotype Play Principal Investigator Prosencephalon Protein Family Proteins Publishing Receptor Activation Receptor Signaling Reporting Rice Role Sensory Severities Signal Pathway Signal Transduction Structure Techniques Testing Thalamic structure Tissue Harvesting Tumor Necrosis Factor Ligand Superfamily Member 6 caspase-8 cytochrome c deprivation disability handicapping condition in vitro Model in vivo injured insight interest neonatal hypoxic-ischemic brain injury neuroprotection programs receptor receptor expression response uptake

项目摘要

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（由申请人提供）：纹状体和丘脑的损伤经常发生在新生儿脑损伤中，并导致感觉运动整合异常，这有助于脑瘫儿童遭受的严重运动，感觉，学习和综合障碍。 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死亡受体是唯一介导坏死和凋亡细胞死亡的唯一已知受体。我们最近报道，在新生儿HI之后，丘脑细胞死亡发生在体内FAS死亡受体途径的多个成分的激活中。此外，我们现在发现，在体外生长的丘脑神经元与皮质神经元和丘脑神经元相比表现出不同的表型，高度富集在FAS死亡受体中。我们的数据表明，FAS死亡受体在发育中的深脑核中延迟神经变性中起着重要作用。通过体内和体外纹状体/丘脑损伤模型，我们将检验以下假设：FAS死亡受体激活是由于低氧 - 缺血性的直接结果，并导致未成熟的丘脑和纹状体中的神经变性。 FAS死亡受体激活改变了细胞内信号传导级联反应，导致各种机制导致细胞死亡：坏死，凋亡和细胞死亡的连续表型。我们将利用免疫组织化学，电子显微镜，生化和分子技术的目标1：确定新生儿HI后深脑核中Fas死亡受体激活的重要性。 AIM 2：确定病理FAS死亡受体激活对促生存和凋亡的细胞内FAS信号通路的影响。 AIM 3：确定在HI之后在体外未成熟的丘脑神经元中Fas死亡受体激活的机制，如氧气剥离所模仿。这些研究将提供对FAS死亡受体介导的窒息脑损伤的发病机理的第一个详细见解，以及对未成熟大脑中神经变性复杂的生物化学的重要见解，这似乎沿坏死的连续体发生在凋亡中。