Regulation of insulin secretion C. elegans

6.项目摘要： 胰岛素分泌和寿命的调节 这个项目的目标是确定调节神经肽分泌的因素， 特别关注胰岛素样生长因子。这个项目的动机是双重的。首先是胰岛素分泌， 及其失调，在衰老、糖尿病和肥胖症中起着关键作用。第二，虽然有很多 我们了解了调节经典神经递质分泌的机制，但对这些机制的了解要少得多。 调节神经肽和激素的分泌。经典的神经递质被包装在突触 囊泡（SV），聚集在活性区。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。SV的分泌发生在活动区， 以快速、阶段性的方式对单一动作电位作出反应。DCV的分泌通常发生在 一系列去极化、融合事件发生在远离活动区的地方，它们发生得相对缓慢， 去极化胞吐作用后，SV池通过胞吞作用在神经末梢迅速重建， SV成分的再循环和神经递质的再填充。相比之下，可释放的DCV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。相对较少 这些差异的生物化学基础是已知的。我们建议确定以下方面所需的因素： 或调节DCV分泌的蛋白质。elegans作为一个模型系统。 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分泌所需的基因。 DCV生物合成、运输或分泌所需。第二，利用RNAi，我们将筛选出大量的基因 (180)这是神经肌肉信号传导对DCV生物发生、运输或分泌的影响所必需的。三是 将表征调节胰岛素分泌的基因和生理条件，并确定 这些途径对寿命和新陈代谢的影响。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。这些基因应该提供了深入了解的机制， 胰岛素调节突触传递和行为。 总之，胰岛素分泌的变化对人类健康有着深远的影响。这些研究 应该提供新的见解细胞机制调节分泌胰岛素和其他 神经肽7.项目叙述： 该提案描述了一套连贯的遗传，分子和生物物理实验，旨在确定 差异调节经典神经递质和神经肽分泌的因子。我们尤其 专注于确定神经元的胰岛素分泌是如何调节的，以及这反过来又是如何调节寿命的， 新陈代谢和行为。这些实验可能会为治疗干预确定新的潜在靶点 糖尿病肥胖和衰老

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.