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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.

首席调查员：德里克·西伯思