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Regulation of insulin secretion C. elegans

胰岛素分泌的调节秀丽隐杆线虫

基本信息

批准号：
8970698
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
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-12-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8970698
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 targeted treatment

项目摘要

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）：该项目的目标是确定一般调节神经肽分泌的因素，并确定这些分泌的肽如何调节行为。该项目的动机有两个。首先，胰岛素分泌及其失调在衰老、糖尿病和肥胖中起着关键作用。其次，虽然人们对调节经典神经递质分泌的机制了解很多，但对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突触小泡（SV）中，突触小泡聚集在活跃区域。神经肽被包装成大而致密的核心囊泡（DCV），并分布在整个轴突和树突中。 SV 的分泌发生在活性区，以快速、阶段性的方式响应单一动作电位。 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发生相对缓慢。胞吐作用后，SV 池通过 SV 成分的内吞再循环在神经末梢快速重建，并重新填充神经递质。相比之下，可释放的 DCV 池必须通过从体细胞顺行运输未成熟的分泌颗粒来重建。对于这些差异的生化基础知之甚少。我们建议使用秀丽隐杆线虫作为模型系统来确定 DCV 分泌所需或调节 DCV 分泌的因素。在初步研究中，我们发现了一种调节睡眠状态唤醒的神经肽。在这里，我们建议确定如何调节该肽的分泌，以及该肽引起唤醒的机制。这些研究应该为调节神经肽睡眠和觉醒分泌的细胞机制提供新的见解。