Multi-scale observation and modeling of IP3/Ca signaling

IP3/Ca 信号传导的多尺度观察和建模

• 批准号: 7278875
• 负责人: JOHN E PEARSON
• 金额: $ 46.39万
• 依托单位: LOS ALAMOS NAT SECTY-LOS ALAMOS NAT LAB
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7278875
• 关键词: Xenopus oocyte; biological models; biological signal transduction; buffers; calcium channel; calcium flux; calcium indicator; calcium ion; confocal scanning microscopy; inositol phosphates; model design /development; voltage /patch clamp

DESCRIPTION (provided by applicant): The liberation of calcium ions from intracellular stores into the cytosol is used as a signaling mechanism by virtually all cell types to regulate functions as diverse as secretion, contraction, proliferation, and cell death. Advances in observational techniques have revealed complex patterns of intracellular Ca2+ that serve to selectively regulate specific cellular responses, and are constructed hierarchically through the activity of individual ion channels, multiple channels within clusters, and interactions between clusters. It is impossible to resolve all these scales simultaneously in a single experiment and the shorter time and distance scales cannot be resolved by any available experimental approaches. We therefore propose to use a tightly integrated approach of modeling, electrophysiology, and high-resolution cellular calcium imaging to illuminate the mechanisms by which "elementary" Ca2+ events are triggered and coupled to produce global cellular calcium signals. Specific aims are to describe (i) the kinetic mechanisms underlying the flux of calcium through single channels, (ii) the functional coupling between individual channels within a cluster, and (iii) the coordination between clusters allowing the propagation of global signals and the effects of buffers on this process. Numerical models will be constructed based on hypotheses and parameter values derived from patch-clamp and confocal cellular imaging experiments, and will be iteratively tested by comparison with observations and by their predictive power. Our overall goal is to develop a comprehensive model of intracellular Ca2+ signaling that is consistent with a multitude of observations, has predictive value, and extends to crucial - but experimentally inaccessible -space and time scales (nanometers and microseconds). We will focus on inositol trisphosphate-mediated Ca2+ signaling, utilizing Xenopus oocytes as a well-characterized model system, but the emergent principles will be widely applicable across many cell types and species, as well as to calcium signalling mediated by ryanodine receptors.

描述（由申请人提供）：从水中释放钙离子 细胞内储存到细胞质中被用作信号传导机制 几乎所有细胞类型都可以调节分泌等多种功能， 收缩、增殖和细胞死亡。观察方面的进展 技术揭示了细胞内 Ca2+ 的复杂模式，这些模式有助于 选择性地调节特定的细胞反应，并构建 通过单个离子通道的活动分层，多个 集群内的通道以及集群之间的交互。这是不可能的 在一次实验中同时解决所有这些尺度 较短的时间和距离尺度无法通过任何可用的解决方案 实验方法。因此，我们建议使用紧密集成的 建模、电生理学和高分辨率细胞钙的方法 成像以阐明“基本”Ca2+ 事件发生的机制 触发并耦合产生全局细胞钙信号。 具体目标是描述（i）钙流动的动力学机制 通过单一渠道，（ii）个体之间的功能耦合 集群内的渠道，以及（iii）集群之间的协调，允许 全局信号的​​传播以及缓冲区对此过程的影响。 将根据假设和参数值构建数值模型 来自膜片钳和共聚焦细胞成像实验，并将 通过与观察结果的比较及其预测进行迭代测试 力量。我们的总体目标是开发细胞内的综合模型 Ca2+ 信号传导与大量观察结果一致， 预测价值，并延伸至关键但实验无法达到的 -空间和时间尺度（纳米和微秒）。我们将专注于肌醇 三磷酸盐介导的 Ca2+ 信号传导，利用非洲爪蟾卵母细胞作为 良好表征的模型系统，但出现的原理将被广泛应用 适用于多种细胞类型和物种以及钙信号传导 由兰尼碱受体介导。