Investigation of calcium signaling in Caenorhabditis elegans

描述（由申请人提供）：概述包括肌肉收缩、转录、细胞分裂和突触囊泡释放。矛盾的是，钙也可以引发细胞死亡和细胞坏死。因此，钙调节失调会以不同的方式和程度影响细胞。因此，钙的含量需要严格调节。事实上，钙信号缺陷与许多神经退行性疾病、肌肉萎缩症和心脏病有关。为了了解钙信号的调控，我们建立了一个新的系统来识别参与细胞内钙水平调控和反应的基因产物。此外，我们已经开发了一种新的制剂来测量体内钙动力学。先前，我们发现VAV-1是Rho家族GTPases的高度进化保守的鸟嘌呤核苷酸交换因子，通过调节钙振荡来调节秀丽隐杆线虫的几种节律行为。这些节律性行为包括咽泵、排卵和受精以及排便。为了了解VAV-1调节钙振荡和这些节律性行为的机制，我们利用秀丽隐杆线虫遗传学的力量来确定其他潜在的钙调节因子。到目前为止，我们的分析已经发现了VAV-1调节细胞内钙储存的释放来调节胞质钙水平的证据。为了阐明VAV-1控制钙信号和节律行为的机制，我们正在采取多方面的方法，包括体内钙成像，结合遗传、分子和细胞生物学技术来探索VAV-1对钙信号的依赖性调节。由于脊椎动物和无脊椎动物之间的信号级联有许多相似之处，并且有证据表明它们在分子，结构和功能水平上具有共性，因此本提案的目标将有助于理解钙信号传导的体内机制。

DESCRIPTION (provided by applicant): Summary including muscle contraction, transcription, cell division, and synaptic vesicle release. Paradoxically, calcium can also trigger cell death and cellular necrosis. Therefore, dysregulation in calcium regulation can affect cells in different ways and to varying degrees. Consequently, the levels of calcium need to be tightly regulated. Indeed, defective calcium signaling has been implicated in many neurodegenerative diseases, muscular dystrophies and heart disease. To understand the regulation of calcium signaling, we have established a novel system to identify gene products involved in the regulation and response to cytosolic calcium levels. Furthermore, we have developed a novel preparation to measure calcium dynamics in vivo. Previously, we found that VAV-1, a highly evolutionarily conserved guanine nucleotide exchange factor for the Rho Family GTPases, regulates several rhythmic behaviors in Caenorhabditis elegans by modulating calcium oscillations. These rhythmic behaviors include pharyngeal pumping, ovulation and fertilization, and defecation. To understand the mechanism(s) VAV-1 utilizes to regulate calcium oscillations and these rhythmic behaviors, we have used the power of C. elegans genetics to identify other potential regulators of calcium. Our analyses thus far have found evidence that VAV-1 modulates the release of calcium from intracellular stores to regulate cytosolic calcium levels. In order to elucidate the mechanisms underlying VAV-1's control of calcium signaling and rhythmic behavior, we are taking a multifaceted approach, which involves in vivo calcium imaging in concert with genetic, molecular and cell biology techniques to explore VAV-1 dependent regulation of calcium signaling. Since there are many similarities between vertebrate and invertebrate signaling cascades and evidence points to their commonality at the molecular, structural and functional level, the goals of this proposal will aid in understanding the in vivo mechanisms involved in calcium signaling. PUBLIC HEALTH RELEVANCE: The regulation of calcium signaling is of paramount importance to many fields, including cardiac and skeletal muscle contraction, synaptic activity, learning and memory, excitotoxicity and cellular necrosis, and aging. Our long-term goals are to resolve the mechanisms that cells use to regulate and decipher calcium signaling using genetic, molecular and cell biological methods.