Genetic Analysis of Neuronal Hypoxic Stress Resistance

神经元耐缺氧应激的遗传分析

基本信息

批准号：
8081758
负责人：
Piya Ghose
金额：
$ 2万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8081758
关键词：
Acute Affect Animals Behavior Brain Brain Injuries Caenorhabditis elegans Calcium Cellular biology Cessation of life Chimeric Proteins Depressed mood Endosomes Face Frequencies Genetic Glutamate Receptor Glutamates Homeostasis Hydroxylation Hypoxia Injury Interneurons Ischemic Stroke Life Lobular Neoplasia Locomotion Mediating Membrane Membrane Protein Traffic Modeling Morbidity - disease rate Movement Mutation Nematoda Neurons Nose Oxidative Stress Oxygen Pathway interactions Phosphorylation Phosphotransferases Physiological Positioning Attribute Prevention Proline Proteins Reaction Receptor Activation Recycling Resistance Signal Pathway Signal Transduction Stress Stroke Synapses Synaptic Membranes System Tertiary Protein Structure Thinking Touch sensation Trauma Traumatic Brain Injury Travel base clinical application disability excitotoxicity genetic analysis in vivo killings loss of function mutation neural circuit neurotransmitter release new therapeutic target novel postsynaptic prevent receptor receptor internalization receptor recycling research study response trafficking

Acute Affect Animals Behavior Brain Brain Injuries Caenorhabditis elegans Calcium Cellular biology Cessation of life Chimeric Proteins Depressed mood Endosomes Face Frequencies Genetic Glutamate Receptor Glutamates Homeostasis Hydroxylation Hypoxia Injury Interneurons Ischemic Stroke Life Lobular Neoplasia Locomotion Mediating Membrane Membrane Protein Traffic Modeling Morbidity - disease rate Movement Mutation Nematoda Neurons Nose Oxidative Stress Oxygen Pathway interactions Phosphorylation Phosphotransferases Physiological Positioning Attribute Prevention Proline Proteins Reaction Receptor Activation Recycling Resistance Signal Pathway Signal Transduction Stress Stroke Synapses Synaptic Membranes System Tertiary Protein Structure Thinking Touch sensation Trauma Traumatic Brain Injury Travel base clinical application disability excitotoxicity genetic analysis in vivo killings loss of function mutation neural circuit neurotransmitter release new therapeutic target novel postsynaptic prevent receptor receptor internalization receptor recycling research study response trafficking

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项目摘要

Traumatic brain injury (TBI) and ischemic stroke are leading causes of morbidity and disability, excitotoxically killing neurons via a combination of hypoxia and oxidative stress, glutamate receptor overactivation, and deregulated calcium homeostasis. In particular, the hypoxia resulting from trauma or stroke results in membrane depolarization and hence release of the neurotransmitter glutamate from affected neurons. High levels of acute glutamate overactivate receptors on neighboring neurons, thereby resulting in calcium influx and excitotoxicity. Agents that directly interfere with receptor activation have had limited clinical applicability because of their dramatic effect on receptor physiological function. Thus, it is important to identify new therapeutic targets in order to mitigate excitotoxicity after TBI or stroke. The discovery that regulated trafficking of glutamate receptors can modify synaptic efficacy has changed the thinking about mechanisms by which receptors contribute to excitotoxicity after neuronal trauma. In particular, the movement of receptors into and out of synaptic membranes after post-trauma hypoxia in some cultured neuronal systems can modulate excitotoxicity. Do changes in glutamate receptor trafficking contribute to neuronal death in the intact animal, or are they part of a neuroprotective response to hypoxia? What factors regulate glutamate receptor trafficking in response to hypoxia? This proposal takes a genetic approach in C. elegans to understand how hypoxia impacts neuron cell biology. In Aim 1, it examines how hypoxia and the known hypoxia response pathway alters the membrane trafficking of receptors. In Aim 2, it characterizes how EGL-9, a PHD protein that senses oxygen levels, regulates LIN-10, a PTB/PDZ-domain protein known to regulate glutamate receptor trafficking, in response to hypoxia. The proposed experiments advance the field in several ways. First, they identify a novel hypoxia response pathway. Second, they demonstrate a new response pathway by which neurons protect themselves from hypoxia. Third, they show that regulated receptor trafficking is the underlying mechanism. Finally, they provide potential new therapeutic targets for minimizing brain damage following TBI and ischemic stroke.

创伤性脑损伤（TBI）和缺血性中风是发病率和残疾的主要原因，通过缺氧和氧化应激，谷氨酸受体过度激活以及失调的钙稳态来兴奋地杀死神经元。特别是，创伤或中风引起的缺氧导致膜去极化，从而从受影响的神经元中释放神经递质谷氨酸。高水平的急性谷氨酸在相邻神经元上过度活化的受体，从而导致钙的流入和兴奋性。直接干扰受体激活的药物由于对受体生理功能的巨大影响而具有有限的临床适用性。因此，重要的是要确定新的治疗靶标，以减轻TBI或中风后的兴奋性毒性。调节谷氨酸受体的运输可以改变突触功效的发现改变了对神经元创伤后受体有助于兴奋性毒性的机制的思考。特别是，在某些培养的神经元系统中创伤后缺氧后受体向突触膜的运动可能调节兴奋性毒性。谷氨酸受体运输的变化是否导致完整动物的神经元死亡，还是对缺氧的神经保护作用的一部分？哪些因素会根据缺氧来调节谷氨酸受体运输？该建议采用秀丽隐杆线虫中的遗传方法，以了解缺氧如何影响神经元细胞生物学。在AIM 1中，它研究了缺氧和已知的缺氧反应途径如何改变受体的膜运输。在AIM 2中，它表征了EGL-9是一种感觉氧气水平的PHD蛋白，调节LIN-10，一种响应缺氧的PTB/PDZ核心蛋白已知可以调节谷氨酸受体运输的PTB/PDZ蛋白蛋白。提出的实验以多种方式推进了该领域。首先，他们确定了一种新型的缺氧反应途径。其次，它们展示了一种新的反应途径，神经元可以保护自己免受缺氧的侵害。第三，他们表明受体贩运是基本机制。最后，它们提供了潜在的新治疗靶标，以最大程度地减少TBI和缺血性中风后的脑损伤。