Regulation of insulin secretion C. elegans

描述(申请人提供)：这个项目的目标是确定调节神经肽分泌的一般因素，并确定这些分泌的多肽如何调节行为。这个项目的动机是双重的。首先，胰岛素分泌及其失调在衰老、糖尿病和肥胖症中起着关键作用。其次，虽然人们对经典神经递质的分泌调节机制已经了解很多，但对那些调节神经肽和激素分泌的机制知之甚少。经典的神经递质被包装在聚集在活动区的突触小泡(SVS)中。神经肽被包装成大而致密的核心小泡(DCV)，分布在轴突和树突中。SVS的分泌在活动区以快速、阶段性的方式发生，对单个动作电位做出反应。DCV的分泌通常发生在一系列去极化之后，融合事件发生在远离活动区的地方，并且在去极化之后发生得相对较慢。胞吐后，SV池在神经末梢通过SV组分的内吞循环和神经递质的补充而迅速重建。相反，可释放的DCV池必须通过顺行运输来自胞体的未成熟分泌颗粒来重建。人们对这些差异的生化基础知之甚少。我们建议使用线虫作为模型系统，确定DCV分泌所需的或调节DCV分泌的因素。在初步研究中，我们确定了一种神经肽，它可以调节睡眠状态下的觉醒。在这里，我们建议确定这种多肽的分泌是如何调节的，以及这种多肽引起觉醒的机制。这些研究应该为调节睡眠和觉醒神经肽分泌的细胞机制提供新的见解。

DESCRIPTION (provided by applicant): The goal of this project is to identify factors that regulate secretion of neuropeptides generally, and to determine how these secreted peptides regulate behavior. The motivation for this project is two-fold. First, insulin secretion, and its misregulation, plays a pivotal role in aging, diabetes, and obesity. Second, while a great deal has been learned about mechanisms regulating secretion of classical neurotransmitters, far less is known about those regulating secretion of neuropeptides and hormones. Classical neurotransmitters are packaged in synaptic vesicles (SVs), which are clustered at active zones. Neuropeptides are packaged into large dense core vesicles (DCVs), and are distributed throughout axons and dendrites. Secretion of SVs occurs at active zones, in a rapid, phasic manner in response to single action potentials. Secretion of DCVs occurs typically after trains of depolarization, fusion events occur far from active zones, and they occur relatively slowly following depolarization. Following exocytosis, the SV pool is rapidly reconstituted at nerve terminals by endocytic recycling of SV components, and refilling with neurotransmitters. By contrast, the releasable pool of DCVs must be reconstituted by anterograde transport of immature secretory granules from the soma. Relatively little is known about the biochemical basis for these differences. We propose to identify factors that are required for or that regulate DCV secretion, using C. elegans as a model system. In preliminary studies, we identify a neuropeptide that regulates arousal from a sleep-like state. Here we propose to determine how secretion of this peptide is regulated, and the mechanism by which this peptide causes arousal. These studies should provide new insights into the cellular mechanisms regulating secretion of neuropeptides sleep, and arousal.