Mechanisms of IP3-dependent Ca++ homestasis regulation

IP3依赖的Ca稳态调节机制

• 批准号: 7585248
• 负责人: Murali Prakriya
• 金额: $ 28.69万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585248
• 关键词: Address; Affect; Alzheimer' s Disease; Animals; Anterior; Behavioral; Behavioral Mechanisms; Biological; Biological Assay; Biological Models; Biological Phenomena; Caenorhabditis elegans; Calcium; Cell physiology; Cells; Chromosomes; Clinical; Complement; Defecation; Defect; Development; Disease; Egtazic Acid; Gap Junctions; Gene Mutation; Genes; Genetic; Goals; Growth; Heparin; Homeostasis; Homologous Gene; Human; Image; Inositol; Intestines; Investigation; Ions; Maps; Molecular; Molecular Genetics; Motor; Mutation; Neurodegenerative Disorders; Neurons; Neurophysiology - biologic function; Organ; Pathogenesis; Pathway interactions; Pattern; Physiological; Play; Process; Property; Regulation; Reporting; Research Personnel; Role; STIM1 gene; Signal Transduction; Solutions; System; TRP channel; Techniques; Testing; Time; base; cell type; culture plates; extracellular; inhibitor/antagonist; insight; mutant; novel; patch clamp; positional cloning; programs; receptor; uptake

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.

描述（由申请人提供）：钙（Ca2+）是无处不在的细胞内信号，负责控制众多细胞过程。该提案的重点是使用秀丽隐杆线虫分子遗传学的能力来理解Ca2+-Homeostasis调节。该建议针对研究细胞间CA +波传播的功能和机制和储存的CA2 +（SOC）通道的功能和机制，这些通道是肌醇1,4,5-三磷酸（IPS）依赖性途径的一部分。在许多不同物种的多种细胞类型中观察到细胞间Ca2+波的传播。已经提出，细胞间Ca2+波在特定器官中的同步细胞活性。我们首先观察到秀丽隐杆线虫肠中的细胞间Ca2+波传播，但根本不知道其功能。由于细胞间Ca2+波传播是一种广泛观察到的生物学现象，因此这可能是使用遗传学研究其机制和功能的重要模型系统。 SOC通道在耗尽细胞内Ca2+存储后，从细胞外溶液中具有重要功能。据推测，SOC流入对神经信号传导和某些神经退行性疾病的发病机理具有重要功能：SOC涌入可能在阿尔茨海默氏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，但它们的分子身份却引起了极大争议。我们将检验以下假设：任何瞬时受体电势通道都是秀丽隐杆线虫肠中的SOC活性。为了研究CA2+稳态，我们通过结合遗传，Ca2+成像和电生理方法来开发独特的测定系统。该系统的独特性可能有助于揭示CA2+稳态的调节机制中的新方面，这些方面在其他系统中无法很好地解决。使用此测定系统，我们将解决以下三个问题1）研究细胞间Ca2+波传播的功能，2）使用反向遗传学识别储存的Ca2+通道，以及3）分离使用远期遗传学影响Ca2+稳态的突变。第二和第三的目标将相互补充，以确定调节Ca2+稳态的重要分子。该项目的完成将提供对由异常CA2+稳态引起的人类疾病的新见解。