Stress Regulation of Synaptic Transmission

 描述（由申请人提供）：氧化应激在与神经退行性疾病相关的认知功能障碍和神经元死亡中起关键作用。Nrf 2是一种在细胞抗氧化应激中起关键作用的转录因子，但对调节脑中Nrf 2活性的生理信号或Nrf 2如何影响神经元功能知之甚少。我的实验室用的是C型。elegans研究调节突触前功能的新信号通路。我们最近确定了Nrf 2同源物SKN-1作为突触前结构和功能的调节因子。我们发现，SKN-1/Nrf 2的功能细胞非自主地调节神经肌肉接头的神经递质分泌。我们还发现，来自神经系统的神经内分泌信号通过激活远端组织中的SKN-1/Nrf 2来赋予生物体范围内的保护免受氧化应激的毒性作用。在这里我们寻求 揭示神经系统和远端组织之间的双向通讯通过调节神经递质分泌促进对氧化应激的适应性反应的细胞和分子机制。在目标1中，我们将确定SKN-1/Nrf 2活性如何通过神经系统释放的神经肽进行正调控。在目标2中，我们将确定活性氧如何促进体内神经肽的释放。在目标3中，我们将确定突触传递如何受到细胞非自主SKN-1激活的负调控。Nrf 2激活在各种神经退行性疾病模型中保护神经元免于死亡，我们的研究可能会发现新的Nrf 2内源性激活剂，这可能会导致开发新的治疗方法，可以预防或治疗这些疾病。

 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.