Stress regulation of neurotransmission

项目摘要 这项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整个生物体的反应 通过调节神经肽的释放来实现氧化应激。氧化应激在认知过程中起着关键作用 与神经退行性疾病相关的功能障碍和神经元死亡，但对 活性氧类在大脑中作为信号分子发挥的生理作用。我的实验室 利用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作为积极调节分泌的信号分子的作用 通过致密核小泡的磺化反应从致密核小泡中分离出特定的神经肽样蛋白 (DCV)释放系数。我们发现，这些神经肽的调节释放激活了 肠道中的抗氧化转录因子SKN-1/NRF2。在这里，我们试图揭开分子 过氧化氢调节DCV释放的机制，以及神经肽信号转导 激活抗氧化剂反应。这项研究将揭示ROS调控的新机制 DCV分泌，这将为氧化还原动态平衡是如何通过 肠道-大脑信号，因此可能与治疗策略的制定直接相关 神经退行性疾病，其进展与不受调节的ROS信号有关。

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.