Stress Regulation of Synaptic Transmission

突触传递的压力调节

基本信息

批准号：
9222832
负责人：
DEREK SIEBURTH
金额：
$ 41.25万
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 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9222832
关键词：
Acute Address Alzheimer&apos s Disease Behavioral Brain Caenorhabditis elegans Cell physiology Cells Cellular Stress Cessation of life Communication Development Disease Disease model Distal Endocrine Feedback Genetic Goals Health Homologous Gene Impaired cognition Inflammation Intestines Laboratories Lead Link Metabolic Modeling Molecular Molecular Genetics Motor Neurons Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neuromuscular Junction Neurons Neuropeptides Neurosecretory Systems Neurotransmitters Onset of illness Organism Oxidative Stress Parkinson Disease Pathway interactions Physiological Play Reactive Oxygen Species Regulation Research Resistance Role Signal Pathway Signal Transduction Signaling Molecule Stress Structure Synaptic Transmission Testing Tissues Toxic effect biological adaptation to stress design in vivo insight neuron loss neurotransmission neurotransmitter release novel novel therapeutics oxidative damage presynaptic prevent research study response synaptic function therapeutic development tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): 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 i 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.

描述（由适用提供）：氧化应激在认知功能障碍和神经退行性疾病中起关键作用。 NRF2是一种转录因子，在细胞对氧化应激的抗性中起关键作用，但我对调节大脑中NRF2活性的物理信号或NRF2如何影响神经元功能几乎一无所知。我的实验室使用秀丽隐杆线虫模型来研究调节突触前功能的新信号通路。我们最近将NRF2同源物SKN-1确定为突触前结构和功能的调节剂。我们发现SKN-1/NRF2函数非自动函数可从神经肌肉连接中调节神经递质分泌。我们还发现，来自神经系统的神经内分泌信号传导通过激活远端组织中的SKN-1/NRF2来赋予生物体范围的保护免受氧化应激的毒性影响。我们在这里寻找为了揭示神经系统和不同时机之间双向通信的细胞和分子机制，通过调节神经递质分泌来促进对氧化物胁迫的适应性反应。在AIM 1中，我们将确定如何通过神经肽从神经系统释放神经肽的正常调节SKN-1/NRF2活性。在AIM 2中，我们将确定活性氧如何在体内促进神经肽释放。在AIM 3中，我们将确定合成传递如何受到细胞非自治SKN-1激活的负调节。 NRF2激活可保护各种神经退行性疾病模型中的神经元死亡，我们的研究可能会发现NRF2的新内源性激活剂，这可能导致可以预防或治疗这些疾病的新疗法的发展。