Stress Regulation of Synaptic Transmission

 描述(申请人提供)：氧化应激在认知功能障碍和与神经退行性疾病相关的神经元死亡中起关键作用。Nrf2是一种转录因子，在细胞抵抗氧化应激中发挥关键作用，但我对调节大脑中Nrf2活动的生理信号或Nrf2如何影响神经元功能知之甚少。我的实验室使用线虫模型来研究调节突触前功能的新信号通路。我们最近发现Nrf2同源基因SKN-1是突触前结构和功能的调节因子。我们发现SKN-1/Nrf2非自主地发挥细胞功能，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/Nrf2，使整个生物体免受氧化应激的毒性影响。我们在这里寻找 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，我们将确定神经系统释放神经肽是如何正向调节SKN-1/Nrf2活性的。在目标2中，我们将确定活性氧物种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激活的负面调节。在各种神经退行性疾病模型中，Nrf2的激活保护神经元免于死亡，我们的研究可能会发现新的Nrf2内源性激活剂，这可能会导致可以预防或治疗这些疾病的新疗法的发展。

 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.