Elementary Events of Intracellular Calcium Signaling
细胞内钙信号传导的基本事件
基本信息
- 批准号:8186416
- 负责人:
- 金额:$ 55.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1992
- 资助国家:美国
- 起止时间:1992-08-01 至 2016-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAlzheimer&aposs DiseaseAmyloidArchitectureBiophotonicsCalciumCalcium OscillationsCalcium SignalingCell DeathCell membraneCell physiologyCellsCessation of lifeComplexComputer softwareCustomCytosolDataDetectionDiffusionDiseaseDyesEndoplasmic ReticulumEventExtracellular FluidFeedbackGated Ion ChannelGenerationsGoalsHeart failureImageImage AnalysisImageryImaging TechniquesImaging technologyIndividualInositolIon Channel GatingIonsKineticsLabelLasersLeadLifeMapsMediatingMembraneMicroscopyMonitorMovementNoiseOpticsPathogenesisPathway interactionsPatternPeptidesPhotobleachingPhysiologicalPlasmaPlayPopulationPredispositionPrionsProcessPropertyProteinsReceptor SignalingRecruitment ActivityRegulationResolutionRoleSecond Messenger SystemsSignal PathwaySignal TransductionSiteSpatial DistributionSpecificitySpottingsSynaptic TransmissionTechniquesTechnologyTimeWritingamyloid peptidebasebrain cellcell motilitycell typeimprovedmillisecondmonomernanonanometerneuronal cell bodynoveloptical imagingphotolysispolyglutaminereceptorrelease of sequestered calcium ion into cytoplasmsecond messengersingle moleculespatiotemporalstoichiometrytechnique developmenttool
项目摘要
DESCRIPTION (provided by applicant): The entry of Ca2+ ions into the cytosol from the extracellular fluid and from endoplasmic reticulum (ER) stores is used as a signaling mechanism by virtually all cell types to regulate functions as diverse as electrical excitability, secretion, proliferation and cell death. Improved optical technology now enables visualization of a hierarchy of Ca2+ signaling events, ranging from openings of single-channel Ca2+-permeable channels ('fundamental' events), concerted openings of clustered channels ('elementary' events) and propagating Ca2+ waves. The localized free [Ca2+] elevations arising through individual and clustered channels serve autonomous signaling functions, and their activity may further be coordinated through Ca2+ diffusion and Ca2+-induced Ca2+ release to propagate global cellular Ca2+ waves. Fundamental and elementary events thus form hierarchical building blocks underlying the complex spatiotemporal Ca2+ signals that permit graded and selective regulation of cell functions. Elucidation of their generation, interaction and functional consequences is, therefore, pivotal to understand the physiological functioning of the ubiquitous Ca2+ messenger pathway and its involvement in disease. Our overall goal is to elucidate, at the single-channel level, how cells generate the hierarchy of Ca2+ signals and how disruptions in Ca2+ signaling may be involved in disease pathogenesis. We focus on physiological Ca2+ signals generated by the ubiquitous inositol trisphosphate second messenger pathway, and on the pathogenic Ca2+-permeable pores formed by amyloid oligomers implicated in Alzheimer's disease. By utilizing novel biophotonic tools that now enable the optical imaging of calcium flux through individual channels and the localization and tracking of channel proteins with nanometer precision we aim to: (i) Further refine optical and analytical techniques for simultaneously monitoring Ca2+ flux through hundreds of individual channels in the plasma membrane and ER of intact cells. (ii) Elucidate how the activity of individual IP3 receptors (IP3R) at a release site is orchestrated to generate elementary Ca2+ puffs. (iii) Employ superresolution imaging techniques to determine the nanoscopic spatial distribution of IP3R, and how this impacts their functioning. (iv) Simultaneously monitor Ca2+ flux and peptide stoichiometry of individual amyloid pores to study fundamental mechanisms of membrane incorporation, channel gating and ion permeation.
PUBLIC HEALTH RELEVANCE: Calcium serves a 'life or death' function in virtually all cells of the body, regulating processes as diverse as the heartbeat and synaptic transmission between brain cells, and disorders in calcium signals are implicated in Alzheimer's and many other diseases. Our goal is to take advantage of recent advances in microscopy that now enable imaging of individual molecules in intact cells to elucidate the hierarchical mechanisms by which calcium signals are generated at levels from single channels to the whole cell, with the dual aims of better understanding their normal functioning and how disruptions in Ca2+ signaling may lead to disease.
描述(由申请人提供):Ca2+离子从细胞外液和内质网(ER)库进入胞质溶胶被用作几乎所有细胞类型的信号传导机制,以调节电兴奋性、分泌、增殖和细胞死亡等多种功能。改进的光学技术现在能够可视化Ca2+信号事件的层次结构,范围从单通道Ca2+渗透通道的开口(“基本”事件),集群通道的协调开口(“基本”事件)和传播Ca2+波。局部游离[Ca2+]升高通过个别和集群通道提供自主信号功能,其活动可能进一步协调通过Ca2+扩散和Ca2+诱导的Ca2+释放传播全球细胞Ca2+波。因此,基本和基本事件形成了复杂的时空Ca2+信号,允许分级和选择性调节细胞功能的分层构建块。因此,阐明它们的产生、相互作用和功能后果对于理解普遍存在的Ca2+信使途径的生理功能及其在疾病中的参与至关重要。我们的总体目标是阐明,在单通道水平上,细胞如何产生Ca2+信号的层次结构,以及Ca2+信号的破坏如何参与疾病的发病机制。我们专注于无处不在的三磷酸肌醇第二信使途径产生的生理Ca2+信号,并在致病性Ca2+渗透孔所形成的淀粉样蛋白低聚物参与阿尔茨海默病。通过利用新的生物光子工具,现在能够通过单个通道的钙流量的光学成像和纳米精度的通道蛋白的定位和跟踪,我们的目标是:(i)进一步完善光学和分析技术,同时监测通过质膜和完整细胞的ER中的数百个单个通道的Ca2+流量。(ii)阐明在释放位点的单个IP3受体(IP3R)的活性如何被协调以产生基本的Ca2+喷流。(iii)采用超分辨率成像技术来确定IP3R的纳米级空间分布,以及这如何影响它们的功能。(iv)同时监测Ca2+流量和单个淀粉样蛋白孔的肽化学计量,以研究膜掺入、通道门控和离子渗透的基本机制。
公共卫生相关性:钙在身体的几乎所有细胞中都起着“生或死”的作用,调节着心跳和脑细胞之间的突触传递等多种过程,钙信号的紊乱与阿尔茨海默氏症和许多其他疾病有关。我们的目标是利用显微镜的最新进展,现在可以对完整细胞中的单个分子进行成像,以阐明钙信号在从单个通道到整个细胞的水平上产生的分层机制,其双重目的是更好地了解它们的正常功能以及Ca2+信号传导的中断如何导致疾病。
项目成果
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IAN PARKER其他文献
IAN PARKER的其他文献
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{{ truncateString('IAN PARKER', 18)}}的其他基金
Elementary Events of Intracellular Calcium Signaling
细胞内钙信号传导的基本事件
- 批准号:
7921729 - 财政年份:2009
- 资助金额:
$ 55.07万 - 项目类别:
Elementary Events of Intracellular Calcium Signaling
细胞内钙信号传导的基本事件
- 批准号:
8537203 - 财政年份:1992
- 资助金额:
$ 55.07万 - 项目类别:
Elementary Events of Intracellular Calcium Signaling
细胞内钙信号传导的基本事件
- 批准号:
8337322 - 财政年份:1992
- 资助金额:
$ 55.07万 - 项目类别:
Elementary Events of Intracellular Calcium Signaling
细胞内钙信号传导的基本事件
- 批准号:
7921910 - 财政年份:1992
- 资助金额:
$ 55.07万 - 项目类别:
SPATIAL AND TEMPORAL ASPECTS OF INSP3 SIGNALING
INSP3 信号的空间和时间方面
- 批准号:
2749919 - 财政年份:1992
- 资助金额:
$ 55.07万 - 项目类别:
ELEMENTARY EVENTS OF INTRACELLULAR CALCIUM SIGNALING
细胞内钙信号传导的基本事件
- 批准号:
2907392 - 财政年份:1992
- 资助金额:
$ 55.07万 - 项目类别:
Elementary Events of Intracellular Calcium Signaling
细胞内钙信号传导的基本事件
- 批准号:
7318697 - 财政年份:1992
- 资助金额:
$ 55.07万 - 项目类别:
Elementary Events of Intracellular Calcium Signaling
细胞内钙信号传导的基本事件
- 批准号:
6924677 - 财政年份:1992
- 资助金额:
$ 55.07万 - 项目类别:
Elementary Events of Intracellular Calcium Signaling
细胞内钙信号传导的基本事件
- 批准号:
7495966 - 财政年份:1992
- 资助金额:
$ 55.07万 - 项目类别:
Elementary Events of Intracellular Calcium Signaling
细胞内钙信号传导的基本事件
- 批准号:
8730157 - 财政年份:1992
- 资助金额:
$ 55.07万 - 项目类别: