Stress regulation of neurotransmission

神经传递的压力调节

• 批准号: 10658235
• 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
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658235
• 关键词: Antioxidants; Axon; Behavioral; Brain; Butyrates; Caenorhabditis elegans; Communication; Cysteine; Dense Core Vesicle; Development; Diet; Distal; Endocrine; Experimental Designs; Genetic; Goals; Homeostasis; Hydrogen Peroxide; Impaired cognition; Intestinal Secretions; Intestines; Laboratories; Link; Mediating; Mitochondria; Modeling; Modification; Molecular; Nervous System; Neurodegenerative Disorders; Neurons; Neuropeptides; Neurosecretion; Nutrient; Organism; Oxidation-Reduction; Oxidative Stress; Physiological; Play; Protein Kinase C; Proteins; Reactive Oxygen Species; Regulation; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Source; Stress; Tissues; Vitamins; Volatile Fatty Acids; experimental study; gut-brain axis; hypocretin; in vivo; insight; neuron loss; neurotransmission; neurotransmitter release; novel; novel therapeutics; receptor; release factor; response; transcription factor; vesicular release; water channel

Project Summary The long-term goal of the proposed research is to identify the mechanisms by which bidirectional communication between the nervous system and the intestine regulates organism-wide responses to oxidative stress through regulated neuropeptide release. Oxidative stress plays a critical role in cognitive dysfunction and neuronal death associated with neurodegenerative diseases, but little is known about the physiological roles that reactive oxygen species play as signaling molecules in the brain. My laboratory uses the model C. elegans to study new signaling pathways that modulate neurotransmitter release. We have identified a role for hydrogen peroxide as a signaling molecule that positively regulates the secretion of specific neuropeptide-like proteins from dense core vesicles through sulfenylation of dense core vesicle (DCV) release factors. We found that the regulated release of these neuropeptides activates the antioxidant transcription factor SKN-1/Nrf2 in the intestine. Here we seek to uncover the molecular mechanisms by which hydrogen peroxide regulates DCV release, and how, in turn, neuropeptide signaling activates the antioxidant response. This study will reveal novel mechanisms underlying ROS regulation of DCV secretion and it will provide fundamental insights into how redox homeostasis is achieved through gut-brain signaling, and may therefore have direct relevance for the development of strategies to treat neurodegenerative diseases whose progression is associated with unregulated ROS signaling.

项目摘要 拟议研究的长期目标是确定双向的机制 神经系统与肠之间的沟通可调节范围内生物的反应 通过调节的神经肽释放，氧化应激。氧化应激在认知中起关键作用 与神经退行性疾病有关的功能障碍和神经元死亡，但对此知之甚少 活性氧的生理作用是大脑中的信号分子。我的实验室 使用秀丽隐杆线虫模型研究调节神经递质释放的新信号通路。我们 已经确定了过氧化氢的作用是一种信号分子，可以正调节分泌 通过致密核心囊泡的磺酰化来自致密核囊泡的特异性神经肽样蛋白 （DCV）释放因素。我们发现这些神经肽的调节释放激活了 肠中的抗氧化转录因子SKN-1/NRF2。在这里，我们试图发现分子 过氧化氢调节DCV释放的机制，以及如何又如何进行神经肽信号传导 激活抗氧化剂反应。这项研究将揭示ROS调节的基本机制 DCV的分泌，它将提供有关如何通过如何实现氧化还原稳态的基本见解 肠道信号传导，因此可能与制定治疗策略具有直接相关性 进展的神经退行性疾病与不受管制的ROS信号传导有关。