Regulation of insulin secretion C. elegans

胰岛素分泌的调节 秀丽隐杆线虫

• 批准号: 8197536
• 负责人: JOSHUA M KAPLAN
• 金额: $ 32.09万
• 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 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197536
• 关键词: Action Potentials; Aging; Axon; Behavior; Biochemical; Biogenesis; Biological Models; Caenorhabditis elegans; Defect; Dendrites; Dense Core Vesicle; Diabetes Mellitus; Event; Exocytosis; Genes; Goals; Health; Hormones; Human; Insulin; Learning; Longevity; Metabolism; Molecular Genetics; Motivation; Names; Nerve; Neurons; Neuropeptides; Neurotransmitters; Obesity; Pathway interactions; Physiological; Play; Principal Investigator; RNA Interference; Recycling; Regulation; Research; Resource Sharing; Role; Secretory Vesicles; Signal Transduction; Somatomedins; Synaptic Transmission; Synaptic Vesicles; Therapeutic Intervention; Training; anterograde transport; base; design; insight; insulin secretion; insulin signaling; neuromuscular; neuronal cell body; programs; reconstitution; research study; response; trafficking

6. Project-Summary: REGULATION OF INSULIN SECRETION AND LIFESPAN The goal of this project is to identify factors that regulate secretion of neuropeptides generally, with a specific focus on insulin-like growth factors. 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. First, we will screen genes that are known to be required for SV secretion to determine which are also required for DCV biogenesis, trafficking, or secretion. Second, using RNAi, we will screen a large set of genes (180) required for neuromuscular signaling for effects on DCV biogenesis, trafficking, or secretion. Third, we will characterize genes and physiological conditions that regulate insulin secretion, and determine the impact of these pathways on lifespan and metabolism. Finally, we will screen known and candidate targets of insulin signaling for defects in synaptic transmission. These genes should provide insights into the mechanisms by which insulin regulates synaptic transmission and behavior. In summary, changes in insulin secretion have profound effects on human health. These studies should provide new insights into the cellular mechanisms regulating secretion of insulin and other neuropeptides. 7. Project Narrative: This proposal describes a coherent set of genetic, molecular, and biophysical experiments designed to identify factors that differentially regulate secretion of classical neurotransmitters and neuropeptides. In particular, we focus on determining how insulin secretion from neurons is regulated, and how this in turn regulates lifespan, metabolism, and behavior. These experiments may identify new potential targets for therapeutic intervention into diabetes, obesity, and aging.

6. 项目概要： 胰岛素分泌和寿命的调节 该项目的目标是确定一般调节神经肽分泌的因素， 特别关注胰岛素样生长因子。该项目的动机有两个。首先，胰岛素分泌， 及其失调，在衰老、糖尿病和肥胖中发挥着关键作用。其次，虽然已经做了很多 了解了调节经典神经递质分泌的机制，但对这些机制知之甚少 调节神经肽和激素的分泌。经典的神经递质被包装在突触中 囊泡（SV），聚集在活性区域。神经肽被包装成大而致密的核心 囊泡（DCV），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、聚变事件发生在远离活动区的地方，并且在以下情况下发生得相对缓慢 去极化。胞吐作用后，SV 库通过内吞作用在神经末梢快速重建 回收 SV 成分，并补充神经递质。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。相对较少 已知这些差异的生化基础。我们建议确定所需的因素 或者使用秀丽隐杆线虫作为模型系统来调节 DCV 分泌。 首先，我们将筛选已知 SV 分泌所需的基因，以确定哪些基因也是 SV 分泌所必需的。 DCV 生物发生、运输或分泌所需的。其次，使用RNAi，我们将筛选大量基因 (180) 是影响 DCV 生物发生、运输或分泌的神经肌肉信号传导所必需的。第三，我们 将表征调节胰岛素分泌的基因和生理条件，并确定 这些途径影响寿命和新陈代谢。最后，我们将筛选已知的和候选的胰岛素靶点 突触传递缺陷的信号传导。这些基因应该通过以下方式提供对机制的见解： 胰岛素调节突触传递和行为。 综上所述，胰岛素分泌的变化对人类健康有着深远的影响。这些研究 应该为调节胰岛素和其他物质分泌的细胞机制提供新的见解 神经肽。 7. 项目叙述： 该提案描述了一系列连贯的遗传、分子和生物物理实验，旨在识别 差异调节经典神经递质和神经肽分泌的因素。特别是，我们 专注于确定如何调节神经元的胰岛素分泌，以及如何调节寿命， 新陈代谢和行为。这些实验可能会确定治疗干预的新潜在目标 糖尿病、肥胖和衰老。