Stress Regulation of Synaptic Transmission

突触传递的压力调节

基本信息

批准号：
8098948
负责人：
DEREK SIEBURTH
金额：
$ 34.73万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
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 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8098948
关键词：
Alzheimer&apos s Disease Biological Models Caenorhabditis elegans Candidate Disease Gene Cell Nucleus Cell physiology Cellular Stress Cholinergic Receptors Family Functional disorder Genes Goals Health Impaired cognition Lead Learning Mediating Metabolic Molecular Motivation Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neuromuscular Junction Neurons Neurotransmitters Onset of illness Orthologous Gene Oxidative Stress Parkinson Disease Pathway interactions Play Presynaptic Terminals Proteins Regulation Regulatory Pathway Role Series Signal Pathway Signal Transduction Stress Synapses Synaptic Transmission Testing Toxin Vertebrates Work biological adaptation to stress body system brain cell functional genomics insight neuronal excitability neuronal survival neurotransmission normal aging novel nrf1 protein presynaptic prevent programs research study response synaptic function transcription factor

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this project is to determine mechanisms by which synaptic transmission is regulated by cellular stress pathways. The motivation of this project is twofold. First, stress plays a critical role in cognitive dysfunction and neurodegeneration associated with neurodegenerative diseases. Second, although much has been learned about how cellular responses to stress can promote neuronal survival, far less is known about how these responses can regulate neuronal function. We propose to characterize the role of a stress response pathway that mediates cellular responses to oxidative stress in regulating synaptic function using C. elegans as a model system. We previously identified a new protein that is conserved in vertebrates, WDR-23, in a functional genomic screen for genes required for synaptic transmission at the neuromuscular junction. We found that WDR-23 promotes the secretion of neurotransmitter from presynaptic terminals by antagonizing the activity of the transcription factor SKN-1. SKN-1 is the ortholog of the mammalian NF-E2 related factor (Nrf) family of transcription factors, which are critical for protecting neurons form the neurodegenerative effects of oxidative stress. We found that skn-1 activity is required for proper neurotransmission and for expression of a neuron-specific gene, acr-2, which encodes an acetylcholine receptor subunit of unknown function. Here we propose to test the hypothesis that SKN-1 regulates synaptic transmission in response to stress. First, we will determine how SKN-1 activity is negatively regulated by WDR-23 and by stress pathways in neurons. Second, we will identify the environmental and cellular stress pathways that activate SKN-1 in neurons. Third, we will determine how SKN-1-activated transcriptional programs generate changes in neurotransmitter secretion and synaptic function. These experiments will provide insights into the molecular mechanisms by which the SKN-1/Nrf stress response pathway regulates synaptic function. In summary, this work will establish a novel role for SKN-1/Nrf-mediated transcriptional programs in regulating synaptic transmission, and should provide insights into how stress impacts synaptic dysfunction associated with neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: Many neurodegenerative disorders, such as Alzheimer's and Parkinson's disease are thought to be caused by toxins that accumulate in brain cells as the result of normal ageing. Here we propose to study how a natural system that the body uses to remove these toxins can impact normal brain cell function, and how it can be used to delay or prevent the onset of these diseases.

描述（由申请人提供）：该项目的长期目标是确定突触传播受细胞应力途径调节的机制。这个项目的动机是双重的。首先，压力在与神经退行性疾病相关的认知功能障碍和神经变性中起关键作用。其次，尽管已经了解了细胞对压力如何促进神经元存活的知识，但对这些反应如何调节神经元功能的了解众所周知。我们建议表征应力反应途径的作用，该途径介导了使用秀丽隐杆线虫作为模型系统调节突触功能中细胞对氧化应激的反应。我们先前鉴定了一种在脊椎动物WDR-23中保守的新蛋白质，该蛋白在神经肌肉连接处突触传播所需的基因的功能基因组筛选中。我们发现WDR-23通过拮抗转录因子SKN-1的活性来促进神经递质从突触前末端的分泌。 SKN-1是转录因子的哺乳动物NF-E2相关因子（NRF）家族的直系同源物，这对于保护神经元至关重要，构成了氧化应激的神经退行性作用。我们发现SKN-1活性是正确的神经传递和表达神经元特异性基因ACR-2的表达所必需的，该基因编码了未知功能的乙酰胆碱受体亚基。在这里，我们建议测试SKN-1响应应力的突触传播的假设。首先，我们将确定如何通过WDR-23和神经元中的应力途径对SKN-1活性负调节。其次，我们将确定激活神经元中SKN-1的环境和细胞应力途径。第三，我们将确定SKN-1激活的转录程序如何产生神经递质分泌和突触功能的变化。这些实验将提供有关SKN-1/NRF应力响应途径调节突触功能的分子机制的见解。总而言之，这项工作将在调节突触传播中为SKN-1/NRF介导的转录程序建立新的作用，并应提供有关压力如何影响与神经退行性疾病相关的突触功能障碍的见解。公共卫生相关性：许多神经退行性疾病，例如阿尔茨海默氏病和帕金森氏病，被认为是由正常衰老导致在脑细胞中积累的毒素引起的。在这里，我们建议研究人体用来去除这些毒素的天然系统如何影响正常的脑细胞功能，以及如何使用它来延迟或防止这些疾病的发作。