Genetics Analysis of Neuronal Hypoxic Stress Resistance

神经元耐缺氧应激的遗传学分析

• 批准号: 8629773
• 负责人: Christopher G Rongo
• 金额: $ 35.61万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629773
• 关键词: Acute; Affect; Animals; Behavior; Behavioral; Binding; Biological; Brain; Brain Injuries; Caenorhabditis elegans; Calcium; Cells; Cellular biology; Cessation of life; Chimeric Proteins; Defect; Depressed mood; Endosomes; Face; Generations; Genes; Genus Mentha; Glutamate Receptor; Glutamates; Hippocampus (Brain); Homeostasis; Hydroxylation; Hypoxia; Hypoxia Inducible Factor; Injury; Interneurons; Ischemic Stroke; Life; Lobular Neoplasia; Locomotion; Mammals; Measurable; Mediating; Mediator of activation protein; Membrane; Membrane Protein Traffic; Mitochondria; Modeling; Molecular Genetics; Morbidity - disease rate; Movement; Mutation; Necrosis; Nematoda; Nerve Degeneration; Neurons; Orthologous Gene; Oxygen; Pathway interactions; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Prevention; Procollagen-Proline Dioxygenase; Production; Proline; Protein Binding; Proteins; Proteomics; Reactive Oxygen Species; Receptor Activation; Recycling; Regulation; Resistance; Signal Transduction; Site; Stress; Stroke; Structure; Surface; Synapses; Synaptic Membranes; System; Tertiary Protein Structure; Testing; Thinking; Trauma; Traumatic Brain Injury; base; clinical application; disability; excitotoxicity; forward genetics; genetic analysis; hypoxia inducible factor 1; in vivo; killings; loss of function mutation; mitochondrial dysfunction; neurotransmitter release; new therapeutic target; novel; postsynaptic; prevent; receptor; research study; response; sensor; trafficking

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) and ischemic stroke are leading causes of morbidity and disability, excitotoxically killing neurons via hypoxia. The underlying mechanism is thought to be a combination of glutamate receptor overactivation, deregulated calcium homeostasis, and mitochondrial dysfunction. Specifically, the hypoxia resulting from trauma or stroke results in membrane depolarization and hence the 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. Mitochondrial dynamics become altered, influencing the production of ATP, as well as the release of calcium and Reactive Oxygen Species (ROS) from neuronal mitochondria. Agents that directly interfere with glutamate 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. Many species, including mammals, have mechanisms by which they protect themselves from glutamate-mediated excitotoxicity, although these mechanisms are poorly understood. Indeed, the movement of glutamate 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? How else does hypoxia alter the cell biology of neurons? This proposal takes genetic, molecular, cell biological, and electrophysiological approaches in C. elegans to understand how hypoxia impacts neuron function. In Aim 1, it examines how hypoxia and components of the known hypoxia response pathway alter the membrane trafficking of receptors. In Aim 2, it characterizes how EGL-9, a prolyl hydroxylase that senses oxygen levels and responds to hypoxia, regulates LIN-10, a PTB/PDZ- domain protein (orthologous to the Mints) known to regulate glutamate receptor trafficking. In Aim 3, it examines how hypoxia and EGL-9 regulate mitochondrial dynamics through their regulation of DRP-1, a mediator of mitochondrial fission. In Aim 4, it examines the effects of this novel pathway on neuron survival in several neurodegenerative models. The proposed experiments advance the field in several ways. First, they identify a novel hypoxia response pathway. Second, they demonstrate how neurons use this novel pathway to protect themselves from hypoxia. Third, they show that regulated receptor trafficking and regulated mitochondrial dynamics are the underlying mechanism. Finally, they provide potential new therapeutic targets for minimizing brain damage following TBI and ischemic stroke.

描述（由申请人提供）：创伤性脑损伤（TBI）和缺血性中风是导致发病和残疾的主要原因，它们通过缺氧产生兴奋性毒性杀死神经元。潜在的机制被认为是谷氨酸受体过度激活、钙稳态失调和线粒体功能障碍的结合。具体来说，创伤或中风引起的缺氧会导致膜去极化，从而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。线粒体动力学改变，影响ATP的产生，以及钙和活性氧（ROS）从神经元线粒体的释放。直接干扰谷氨酸受体激活的药物由于其对受体生理功能的显著影响，其临床适用性有限。因此，确定新的治疗靶点以减轻脑外伤或脑卒中后的兴奋性毒性是很重要的。谷氨酸受体的调节运输可以改变突触的功效，这一发现改变了人们对神经元创伤后受体参与兴奋性毒性机制的思考。许多物种，包括哺乳动物，都有保护自己免受谷氨酸介导的兴奋性毒性的机制，尽管这些机制尚不清楚。事实上，在一些培养的神经元系统中，创伤后缺氧后谷氨酸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导致了完整动物的神经元死亡