Stress Regulation of Synaptic Transmission

突触传递的压力调节

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

首席研究员：德里克·西伯斯（Derek Sieburth）项目摘要拟议研究的长期目标是确定双向的机制神经系统与远端组织之间的通信调节范围内的生物的反应氧化应激。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。 NRF2是转录因子，在细胞中起关键作用对氧化应激的抗性，但对调节NRF2活性的生理信号知之甚少在大脑中或NRF2如何影响神经元功能。我的实验室使用e秀隐杆线虫来研究新的调节突触前功能的信号通路。我们最近确定了NRF2同源物SKN-1，作为突触前结构和功能的调节剂。我们发现SKN-1/NRF2功能细胞非 - 自主来调节神经肌肉连接的神经递质分泌。我们还发现神经系统的神经内分泌信号转导范围范围通过激活远端组织中的SKN-1/NRF2来激活氧化应激。在这里，我们试图发现细胞和神经系统与远端之间双向通信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。在AIM 1中，我们将确定如何通过神经肽对SKN-1/NRF2活性进行积极调节从神经系统中释放。在AIM 2中，我们将确定活性氧如何促进神经肽在体内释放。在AIM 3中，我们将确定如何对突触传播进行负调节通过细胞非自主SKN-1激活。 NRF2激活保护神经元形成多种死亡神经退行性疾病模型，我们的研究可能会发现NRF2的新内生激活剂这可能导致可以预防或治疗这些疾病的新疗法的发展。