Mechanisms of IP3-dependent Ca++ homestasis regulation

描述（由申请人提供）：钙（Ca 2+）是一种普遍存在的细胞内信号，负责控制许多细胞过程。该建议的重点是理解利用C的力量进行的Ca 2+稳态调节。分子遗传学本研究旨在探讨细胞间钙波传播和钙库操纵的钙通道（SOC）的功能和机制，SOC是三磷酸肌醇（IPS）依赖性途径的一部分。细胞间Ca ~（2+）波的传播在许多不同物种的多种细胞类型中被观察到。有人提出细胞间Ca ~（2+）波在特定器官中起着同步细胞活动的作用。我们首次观察到了C. elegans肠，但其功能尚不清楚。由于细胞间Ca ~（2+）波传播是一种广泛观察到的生物学现象，这可能是利用遗传学研究其机制和功能的重要模型系统。SOC通道在细胞内Ca 2+库耗尽后从细胞外溶液中摄取Ca 2+具有重要功能。推测SOC内流在神经信号转导和某些神经退行性疾病的发病机制中具有重要作用：SOC内流可能在阿尔茨海默病的早期发展中起重要作用。尽管SOC通道具有生物学和临床重要性，但其分子身份仍存在很大争议。我们将检验任何瞬时受体电位通道负责C.线虫肠为了研究Ca 2+稳态，我们开发了一种独特的分析系统，结合遗传，Ca 2+成像，和电生理的方法。该系统的独特性可能有助于揭示Ca 2+稳态调节机制的新方面，这在其他系统中无法很好地解决。使用该检测系统，我们将解决以下三个问题：1）研究细胞间Ca 2+波传播的功能，2）使用反向遗传学鉴定钙池操纵的Ca 2+通道，3）使用正向遗传学分离影响Ca 2+稳态的突变。第二个和第三个目标将相辅相成，以确定调节Ca 2+稳态的重要分子。该项目的完成将为研究由异常Ca 2+稳态引起的人类疾病提供新的见解。

DESCRIPTION (provided by applicant): Calcium (Ca2+) is a ubiquitous intracellular signal, which is responsible for controlling numerous cellular processes. This proposal focuses on understanding of Ca2+-homeostasis regulation using the power of C. elegans molecular genetics. This proposal is directed toward an investigation of functions and mechanisms of the intercellular Ca +-wave propagation and the store-operated Ca2+ (SOC) channels, which are part of the inositol 1,4,5-trisphosphate (IPS)-dependent pathway. The intercellular Ca2+-wave propagation is observed in a variety of cell types in many different species. It has been proposed that the intercellular Ca2+ waves function as synchronizing cellular activities in a particular organ. We first observed the intercellular Ca2+-wave propagation in C. elegans intestine, but its function is not known at all. Since intercellular Ca2+-wave propagation is a widely observed biological phenomena, this can be an important model system to investigate its mechanism and function using genetics. The SOC channels have an important function for Ca2+ uptake from the extracellular solution upon depletion of intracellular Ca2+ stores. It is speculated that the SOC influx has an important function for neural signaling and the pathogenesis of some neurodegenerative diseases: SOC influx may play an important role in the early development of Alzheimer's disease. Despite the biological and clinical importance of the SOC channels, their molecular identity is highly controversial. We will test the hypothesis that any transient receptor potential channels are responsible for the SOC activity in the C. elegans intestine. To study Ca2+ homeostasis, we developed a unique assay system by combining genetic, Ca2+-imaging, and electrophysiological approaches. This uniqueness of the system could contribute to revealing new aspects in the regulatory mechanisms of Ca2+ homeostasis, which were not able to be addressed well in other systems. Using this assay system, we will address the following three issues 1) investigating the function of the intercellular Ca2+-wave propagation, 2) identifying the store-operated Ca2+ channels using reverse genetics, and 3) isolation of mutations that affect Ca2+ homeostasis using forward genetics. The second and third aims will complement each other to identify important molecules for regulation of Ca2+ homeostasis. Completion of this project will provide new insights into human disorders that are caused by abnormal Ca2+ homeostasis.