Regulation of insulin secretion C. elegans

胰岛素分泌的调节 秀丽隐杆线虫

• 批准号: 8774901
• 负责人: JOSHUA M KAPLAN
• 金额: $ 41.83万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8774901
• 关键词: Acetylcholine; Action Potentials; Adenylate Cyclase; Aging; Arousal; Axon; Behavior; Biochemical; Biological Assay; Biological Models; Biology; Caenorhabditis elegans; Coupled; Cyclic AMP-Dependent Protein Kinases; Data; Dendrites; Dense Core Vesicle; Diabetes Mellitus; Disease; Distal; Event; Exocytosis; Gene Silencing; Genes; Goals; Health; Hormones; Imaging Techniques; Learning; Locomotion; Mediating; Mental disorders; Metabolic Diseases; Molecular Genetics; Motivation; Mutation; Nerve; Neuromuscular Junction; Neurons; Neuropeptide Receptor; Neuropeptides; Neurotransmitters; Obesity; Paper; Pathway interactions; Peptides; Phenotype; Play; Proteins; RNA Interference; Recycling; Regulation; Role; Secretory Vesicles; Series; Sleep; Sleep Disorders; Sleeplessness; Synaptic Vesicles; Testing; Therapeutic Intervention; Touch sensation; Training; Vesicle; anterograde transport; base; design; insight; insulin secretion; mutant; neuronal cell body; receptor; reconstitution; research study; response

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.

描述（由申请人提供）：本项目的目标是鉴定通常调节神经肽分泌的因子，并确定这些分泌的肽如何调节行为。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。第二，虽然人们对调节经典神经递质分泌的机制已经了解了很多，但对调节神经肽和激素分泌的机制却知之甚少。经典的神经递质被包装在突触囊泡（SV）中，这些囊泡聚集在活性区。神经肽被包装成大的致密核心囊泡（DCV），并且分布在整个轴突和树突中。SV的分泌发生在活动区，以快速、阶段性的方式响应单个动作电位。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，并且它们在去极化之后相对缓慢地发生。胞吐作用后，SV池通过SV组分的内吞再循环在神经末梢迅速重建，并重新填充神经递质。相比之下，DCV的可释放池必须通过来自索马的未成熟分泌颗粒的顺行运输来重建。对于这些差异的生物化学基础知之甚少。我们建议使用C. elegans作为一个模型系统。在初步研究中，我们确定了一种神经肽，它可以调节从睡眠状态唤醒。在这里，我们建议确定如何分泌这种肽的调节，以及这种肽引起唤醒的机制。这些研究将为调节神经肽分泌、睡眠和觉醒的细胞机制提供新的见解。