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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

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和残疾的主要原因，通过缺氧和氧化应激、谷氨酸受体过度活化和钙稳态失调的组合兴奋性毒性杀死神经元。特别是，由创伤或中风引起的缺氧导致膜去极化，因此从受影响的神经元释放神经递质谷氨酸。高水平的急性谷氨酸过度激活邻近神经元上的受体，从而导致钙内流和兴奋性毒性。直接干扰受体活化的药物由于其对受体生理功能的显著影响而具有有限的临床应用性。因此，重要的是要确定新的治疗靶点，以减轻TBI或中风后的兴奋性毒性。谷氨酸受体的调节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促进兴奋性毒性的机制的思考。特别是，在一些培养的神经元系统中，在创伤后缺氧后受体进出突触膜的运动可以调节兴奋性毒性。谷氨酸受体运输的变化是否会导致完整动物的神经元死亡，或者它们是对缺氧的神经保护反应的一部分？什么因素调节谷氨酸受体运输对缺氧的反应？该提案采用了C中的遗传方法。elegans了解缺氧如何影响神经元细胞生物学。在目标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。在目的2中，它表征了EGL-9（一种感测氧水平的PHD蛋白）如何调节LIN-10（一种已知调节谷氨酸受体运输的PTB/PDZ结构域蛋白）以响应缺氧。拟议中的实验在几个方面推动了该领域的发展。首先，他们确定了一种新的缺氧反应途径。其次，它们展示了一种新的反应途径，神经元通过这种途径保护自己免受缺氧。第三，它们表明受调节的受体运输是潜在的机制。最后，它们提供了潜在的新的治疗靶点，以最大限度地减少TBI和缺血性卒中后的脑损伤。