Regulation of insulin secretion C. elegans

6.项目--总结： 胰岛素分泌调节与寿命 这个项目的目标是确定调节神经肽分泌的一般因素， 特别关注胰岛素样生长因子。这个项目的动机是双重的。首先，胰岛素分泌， 以及它的错误调控，在衰老、糖尿病和肥胖症中起着关键作用。第二，虽然已经有了很大一部分 了解了调节经典神经递质分泌的机制后，人们对此知之甚少 调节神经肽和激素的分泌。经典的神经递质包装在突触中 囊泡(SVs)，聚集在活动区。神经肽被包装成大而致密的核心 囊泡(DCV)，分布于轴突和树突。SVS的分泌发生在活动区， 以快速、分阶段的方式对单个动作电位作出反应。DCV的分泌通常发生在 一连串的去极化、聚变事件发生在远离活动区的地方，它们发生的速度相对较慢 去极化。胞吐后，SV池在神经末梢通过内吞迅速重建。 回收SV成分，并补充神经递质。相比之下，可释放的DCV池 必须通过顺行运输来自胞体的未成熟分泌颗粒来重组。相对较少 已知这些差异的生物化学基础。我们建议确定以下因素： 或者，以线虫为模型系统，调节DCV的分泌。 首先，我们将筛选已知的SV分泌所需的基因，以确定哪些基因也是 DCV生物发生、贩运或分泌所必需的。其次，使用RNAi，我们将筛选一大组基因 (180)神经肌肉信号对DCV生物发生、运输或分泌的影响。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 这些途径与寿命和新陈代谢有关。最后，我们将筛选胰岛素的已知和候选靶点。 突触传递缺陷的信号。这些基因应该通过以下方式提供对机制的洞察 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的分泌的细胞机制提供新的见解 神经肽。7.项目说明： 这项建议描述了一套连贯的遗传、分子和生物物理实验，旨在识别 调节经典神经递质和神经肽分泌的不同因素。特别是，我们 重点是确定神经元的胰岛素分泌是如何调节的，以及这又是如何调节寿命的， 新陈代谢和行为。这些实验可能为治疗干预确定新的潜在靶点。 糖尿病、肥胖症和衰老。

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.