Genetics Analysis of Neuronal Hypoxic Stress Resistance
神经元耐缺氧应激的遗传学分析
基本信息
- 批准号:8650508
- 负责人:
- 金额:$ 4.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcuteAffectAnimalsBehaviorBehavioralBindingBiologicalBrainBrain InjuriesCaenorhabditis elegansCalciumCellsCellular biologyCessation of lifeChimeric ProteinsDefectDepressed moodEndosomesFaceGenerationsGenesGeneticGenus MenthaGlutamate ReceptorGlutamatesHippocampus (Brain)HomeostasisHydroxylationHypoxiaHypoxia Inducible FactorInjuryInterneuronsIschemic StrokeLifeLobular NeoplasiaLocomotionMammalsMeasurableMediatingMediator of activation proteinMembraneMembrane Protein TrafficMitochondriaModelingMolecular GeneticsMorbidity - disease rateMovementMutationNecrosisNematodaNerve DegenerationNeuronsOrthologous GeneOxygenPathway interactionsPhosphorylationPhosphorylation SitePhosphotransferasesPhysiologicalPreventionProcollagen-Proline DioxygenaseProductionProlineProtein BindingProteinsProteomicsReactive Oxygen SpeciesReceptor ActivationRecyclingRegulationResistanceSignal TransductionSiteStressStrokeStructureSurfaceSynapsesSynaptic MembranesSystemTertiary Protein StructureTestingThinkingTraumaTraumatic Brain Injurybaseclinical applicationdisabilityexcitotoxicitygenetic analysishypoxia inducible factor 1in vivokillingsloss of function mutationmitochondrial dysfunctionneurotransmitter releasenew therapeutic targetnovelpostsynapticpreventreceptorresearch studyresponsesensortrafficking
项目摘要
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)和缺血性中风是发病率和残疾的主要原因,兴奋地通过缺氧杀死神经元。潜在的机制被认为是谷氨酸受体过度活化,失控的钙稳态和线粒体功能障碍的组合。具体而言,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。线粒体动力学发生了改变,影响了ATP的产生,以及从神经元线粒体中释放钙和活性氧(ROS)。直接干扰谷氨酸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。许多物种,包括哺乳动物,具有保护自己免受谷氨酸介导的兴奋性毒性的机制,尽管这些机制知之甚少。实际上,在某些培养的神经元系统中创伤后缺氧后,谷氨酸受体向突触膜中的运动可以调节兴奋性。谷氨酸受体运输的变化会导致完整动物的神经元死亡,或者是
它们是对缺氧的神经保护反应的一部分?哪些因素会根据缺氧来调节谷氨酸受体运输?缺氧还如何改变神经元的细胞生物学?该建议采用秀丽隐杆线虫中的遗传,分子,细胞生物学和电生理方法,以了解缺氧如何影响神经元功能。在AIM 1中,它研究了已知缺氧反应途径的缺氧和成分如何改变受体的膜运输。在AIM 2中,它表征了EGL-9是一种感知氧气水平并对缺氧反应的丙酰羟化酶,调节LIN-10,一种已知的PTB/PDZ-域蛋白(与薄荷型)的PTB/PDZ域蛋白(与薄荷型)调节有关调节谷氨酸受体运输。在AIM 3中,它检查了缺氧和EGL-9如何通过调节DRP-1(线粒体裂变介质)调节线粒体动力学。在AIM 4中,它研究了这种新途径对几种神经退行性模型中神经元存活的影响。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,他们证明了神经元如何使用这种新型途径来保护自己免受缺氧的侵害。第三,他们表明受体运输和调节的线粒体动力学是基本机制。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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Christopher G Rongo其他文献
Christopher G Rongo的其他文献
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$ 4.92万 - 项目类别:
Multi-Omic Analysis of BMP-Insulin Signaling Crosstalk in Lipid Metabolism during Aging
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10553134 - 财政年份:2022
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Genetic Analysis of Neuronal Hypoxic Stress Resistance
神经元耐缺氧应激的遗传分析
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9753252 - 财政年份:2012
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$ 4.92万 - 项目类别:
Genetic Analysis of Neuronal Hypoxic Stress Resistance
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9979647 - 财政年份:2012
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$ 4.92万 - 项目类别:
Genetics Analysis of Neuronal Hypoxic Stress Resistance
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8457043 - 财政年份:2012
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$ 4.92万 - 项目类别:
Genetics Analysis of Neuronal Hypoxic Stress Resistance
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