Stress regulation of neurotransmission

项目摘要 拟议研究的长期目标是确定双向 神经系统和肠道之间的通讯调节生物体对 氧化应激通过调节神经肽释放。氧化应激在认知过程中起着至关重要的作用， 功能障碍和神经元死亡与神经退行性疾病，但鲜为人知的是， 活性氧在大脑中作为信号分子发挥的生理作用。我的实验室 使用模型C。elegans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作为信号分子的作用， 通过致密核心囊泡的磺酰化从致密核心囊泡中提取特异性神经肽样蛋白 (DCV)释放因子我们发现这些神经肽的调节释放激活了 抗氧化转录因子SKN-1/Nrf 2在肠道中的作用。在这里，我们试图揭示分子 过氧化氢调节DCV释放的机制，以及神经肽信号传导 激活抗氧化反应。这项研究将揭示新的机制，潜在的活性氧调节， DCV分泌，它将提供基本的见解如何氧化还原稳态是通过 肠-脑信号传导，因此可能与治疗策略的发展直接相关 其进展与不受调节的ROS信号传导相关的神经变性疾病。

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.