Neuron-glia interactions in regulation of activity-dependent signaling pathways

神经元-胶质细胞相互作用调节活性依赖性信号通路

基本信息

批准号：
8890248
负责人：
MARTA MARGETA
金额：
$ 33.8万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8890248
关键词：
Address Affect Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Animals Antioxidants Astrocytes Attenuated Biochemical Biological Biology Blood - brain barrier anatomy Brain Cells Chemosensitization Coculture Techniques Complex Data Development Disease Drug Design Drug Metabolic Detoxication Environment Environmental Risk Factor Enzymes Feedback Fostering Foundations Functional disorder Future Genetic Glutamates Goals Hippocampus (Brain)In Vitro Individual Injury Knock-out Knowledge Laboratories Learning Mediating Mediator of activation protein Metabolic Mission Mitochondria Molecular Molecular Target N-Methyl-D-Aspartate Receptors Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Oxidative Stress Parkinson Disease Pathogenesis Pathway interactions Pharmaceutical Preparations Phase Physiology Play Potassium Channel Predisposition Prevention Process Public Health Reactive Oxygen Species Receptor Signaling Regulation Research Resistance Role Second Messenger Systems Shapes Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Slice Stroke Synapses Synaptic Transmission Synaptic plasticity Testing Toxin Transgenic Mice United States National Institutes of Health Work base cell type cellular targeting density excitotoxicity improved innovation mouse model nervous system disorder neuroprotection neurotoxicity neurotransmission protein aggregation response second messenger synaptic function

Address Affect Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Animals Antioxidants Astrocytes Attenuated Biochemical Biological Biology Blood - brain barrier anatomy Brain Cells Chemosensitization Coculture Techniques Complex Data Development Disease Drug Design Drug Metabolic Detoxication Environment Environmental Risk Factor Enzymes Feedback Fostering Foundations Functional disorder Future Genetic Glutamates Goals Hippocampus (Brain)In Vitro Individual Injury Knock-out Knowledge Laboratories Learning Mediating Mediator of activation protein Metabolic Mission Mitochondria Molecular Molecular Target N-Methyl-D-Aspartate Receptors Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Oxidative Stress Parkinson Disease Pathogenesis Pathway interactions Pharmaceutical Preparations Phase Physiology Play Potassium Channel Predisposition Prevention Process Public Health Reactive Oxygen Species Receptor Signaling Regulation Research Resistance Role Second Messenger Systems Shapes Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Slice Stroke Synapses Synaptic Transmission Synaptic plasticity Testing Toxin Transgenic Mice United States National Institutes of Health Work base cell type cellular targeting density excitotoxicity improved innovation mouse model nervous system disorder neuroprotection neurotoxicity neurotransmission protein aggregation response second messenger synaptic function

展开

项目摘要

DESCRIPTION (provided by applicant): Oxidative stress plays an important role in the pathogenesis of neurodegenerative diseases and stroke. However, low levels of reactive oxygen species (ROS) function as second messengers in many neuronal signal transduction pathways, which could thus be affected either by the disease process itself or by activation of endogenous antioxidant responses. The long term goal of this research is to define how endogenous antioxidant signaling regulates synaptic transmission and thus shapes vulnerability of synaptic networks to oxidative stress. The specific objective of this application is to elucidate molecular mechanisms underlying synaptic function of Nrf2, the transcriptional regulator of inducible antioxidant response that is a key determinant of neuronal susceptibility to injury. Our central hypothesis is that astrocytes respond to neuronal activity by enhancing current flow through ROS-sensitive glutamatergic NMDA receptors (NMDARs, the key mediators of both synaptic plasticity and glutamate excitotoxicity), while simultaneously activating Nrf2 pathway to protect neurons from ROS-induced damage and neurotoxicity. This hypothesis was formulated on the basis of the strong preliminary data obtained in our laboratory and will be tested by pursuing four specific aims. First, we will elucidate the molecular mechanism that underlies activity-mediated induction of Nrf2 pathway in neuron-astrocyte co-cultures. Second, we will establish whether neuroprotection induced by synaptic activity is enhanced when neurons are co-cultured with astrocytes. Third, we will determine how glial cells increase neuronal NMDAR current density in the mixed neuron-glia environment. Fourth, we will dissect the neuron-glia signal transduction cascade that underlies Nrf2-mediated regulation of NMDAR signaling and determine the effect of Nrf2 pathway activation on circuit plasticity. These aims will be accomplished through a combination of molecular, biochemical, electrophysiological, cell biological, and toxicological approaches whose feasibility in our hands has been established through the preliminary data; to dissect the roles of individual cell types, we will use primary neuronal, glial, and mixed hippocampal cultures, as well as neuron-glia co-cultures of defined cellular composition. The overall approach takes the field in a new direction by focusing on the role of neuron- glia interactions in the regulation and function of Nrf2 signaling in the brain, an aspect of Nrf2 biology that has not yet been investigated. Completion of the proposed research is expected to advance our understanding of ROS signaling and Nrf2 physiology in the brain; ultimately, such knowledge will enable development of pharmacologic treatments capable of harnessing neuroprotective power of endogenous antioxidants without negatively affecting neuronal activity and synaptic signaling.

描述（由申请人提供）：氧化应激在神经退行性疾病和中风的发病机理中起重要作用。然而，低水平的活性氧（ROS）在许多神经元信号转导途径中充当第二使者，因此，这可能会受到疾病过程本身或激活内源性抗氧化剂反应的影响。这项研究的长期目标是定义内源性抗氧化信号如何调节突触传播，从而塑造突触网络对氧化应激的脆弱性。该应用的具体目标是阐明NRF2的突触功能的分子机制，NRF2是诱导抗氧化剂反应的转录调节剂，这是神经元易感性损伤的关键决定因素。我们的核心假设是，星形胶质细胞通过增强通过ROS敏感的谷氨酸能NMDA受体的流动来反应神经元活性（NMDARS，是突触可塑性和谷氨酸兴奋性毒性毒性的关键介体），同时激活NRF2途径，以保护NRF2途径，以保护神经元免受玫瑰毒性的损害和Neurotoxic的损害。该假设是根据在我们的实验室中获得的强大初步数据提出的，并将通过追求四个具体目标来测试。首先，我们将阐明活性介导的NRF2途径在神经元 - 胃细胞共培养中诱导的分子机制。其次，我们将确定当神经元与星形胶质细胞共培养时，突触活性诱导的神经保护是否会增强。第三，我们将确定在混合神经元环境中，神经胶质细胞如何增加神经元NMDAR电流密度。第四，我们将剖析NRF2介导的NMDAR信号调节的基础的神经元-GLIA信号转导级联，并确定NRF2途径激活对电路可塑性的影响。这些目标将通过分子，生化，电生理，细胞生物学和毒理学方法的结合来实现，这些方法已经通过初步数据确定了我们手中的可行性；为了剖析单个细胞类型的作用，我们将使用原发性神经元，神经胶质和混合海马培养物，以及定义的细胞组成的神经元间培养。总体方法通过重点关注神经元素相互作用在大脑中NRF2信号的调节和功能中的作用来朝着新的方向发展，NRF2生物学的一个方面尚未研究。预计拟议的研究的完成将提高我们对大脑中ROS信号传导和NRF2生理学的理解。最终，这种知识将能够发展能够利用内源性抗氧化剂神经保护能力的药物治疗，而不会对神经元活性和突触信号传导产生负面影响。