Stress Regulation of Synaptic Transmission

突触传递的压力调节

• 批准号: 9220469
• 负责人: DEREK SIEBURTH
• 金额: $ 36.09万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9220469
• 关键词: Alzheimer' s Disease; Animals; Behavioral; Brain; Caenorhabditis elegans; Cell physiology; Cells; Cessation of life; Communication; Development; Disease; Disease model; Distal; Endocrine; Gene Targeting; Generations; Genetic; Goals; Health; Homologous Gene; Impaired cognition; Inflammation; Intestines; Laboratories; Lead; Link; Mammals; Modeling; Molecular; Motor; Mutation; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neuromuscular Junction; Neurons; Neuropeptides; Neurosecretory Systems; Neurotransmitters; Nuclear; Organism; Oxidative Stress; Parkinson Disease; Pathway interactions; Physiological; Play; Principal Investigator; Proteins; Reactive Oxygen Species; Regulation; Research; Resistance; Role; Signal Pathway; Signal Transduction; Sphingolipids; Stress; Structure; Synapses; Synaptic Transmission; Tissues; Toxic effect; biological adaptation to stress; design; experimental study; in vivo; motor neuron function; neuron loss; neuronal survival; neurotransmission; neurotransmitter release; novel therapeutics; presynaptic; prevent; receptor; response; synaptic function; transcription factor

Principal Investigator: Derek Sieburth Project Summary The long-term goal of the proposed research is to identify the mechanisms through which bidirectional communication between the nervous system and distal tissues regulates organism-wide responses to oxidative stress. Oxidative stress plays a critical role in cognitive dysfunction and neuronal death associated with neurodegenerative diseases. Nrf2 is a transcription factor that plays a key role in cellular resistance to oxidative stress, but little is known about the physiological signals that regulate Nrf2 activity in the brain or how Nrf2 impacts neuronal function. My laboratory uses the model C. elegans to study new signaling pathways that modulate presynaptic function. We recently identified the Nrf2 homolog, SKN-1, as a regulator of presynaptic structure and function. We found that SKN-1/Nrf2 functions cell non- autonomously to regulate neurotransmitter secretion from neuromuscular junctions. We also found that neuroendocrine signaling from the nervous system confers organism-wide protection from the toxic effects of oxidative stress by activating SKN-1/Nrf2 in distal tissues. Here we seek to uncover the cellular and molecular mechanisms by which bidirectional communication between the nervous system and distal tissues promotes an adaptive response to oxidative stress through the regulation of neurotransmitter secretion. In Aim 1, we will determine how SKN-1/Nrf2 activity is positively regulated by neuropeptide release from the nervous system. In Aim 2, we will determine how reactive oxygen species promote neuropeptide release in vivo. In Aim 3 we will determine how synaptic transmission is negatively regulated by cell non-autonomous SKN-1 activation. Nrf2 activation protects neurons form death in a variety of neurodegenerative disease models, and our research may uncover new endogenous activators of Nrf2, which may lead to the development of new therapeutics that can prevent or treat these diseases.

主要研究者：Derek Sieburth 项目摘要 拟议研究的长期目标是确定双向 神经系统和远端组织之间的通讯调节生物体范围内的反应， 氧化应激氧化应激在认知功能障碍和神经元死亡中起关键作用 与神经退行性疾病有关。Nrf 2是一种转录因子，在细胞内起关键作用， 抗氧化应激，但对调节Nrf 2活性的生理信号知之甚少 或者Nrf 2如何影响神经元功能。我的实验室用的是C型。elegans研究新 调节突触前功能的信号通路。我们最近发现了Nrf 2的同源物SKN-1， 作为突触前结构和功能的调节器。我们发现，SKN-1/Nrf 2功能细胞非- 自主调节神经肌肉接头的神经递质分泌。我们还发现 来自神经系统的神经内分泌信号赋予生物体范围的保护免受毒性作用 通过激活远端组织中的SKN-1/Nrf 2来抑制氧化应激。在这里，我们试图揭示细胞和 神经系统和远端神经系统之间双向通讯的分子机制 组织通过调节神经递质促进对氧化应激的适应性反应 分泌物在目的1中，我们将确定SKN-1/Nrf 2活性是如何被神经肽正向调节的， 从神经系统中释放出来。在目标2中，我们将确定活性氧如何促进 体内神经肽释放。在目标3中，我们将确定突触传递是如何负调控的 SKN-1细胞非自主激活。Nrf 2激活保护神经元免于死亡， 神经退行性疾病模型，我们的研究可能会发现新的Nrf 2内源性激活剂， 这可能会导致新的治疗方法的发展，可以预防或治疗这些疾病。