Multi-scale observation and modeling of IP3/Ca signaling

摘要 该项目的总体目标涉及多尺度建模和实验的协同方法 观察，以阐明细胞钙信号转导的基本机制。胞质ca2 + 瞬变作为调节如分泌一样多样的细胞功能的普遍存在的信号传导机制， 收缩和增殖。信息由细胞质Ca 2+信号的时空模式编码， 尺度从纳米和微秒到毫米和分钟，涉及Ca2+的"音素" 通过单个通道的活动分层构建;集群内的多个通道;以及 集群之间的互动。这些水平不能同时观察到任何单一的实验 技术和较短的尺度低于实验分辨率。因此，我们采用了双重，紧密 数据驱动的数学建模与实验的集成和迭代方法 包括电生理单通道记录和高分辨率细胞Ca2+测量 成像以阐明涉及单个通道和簇的"基本" Ca2+事件如何被触发， 耦合产生全局细胞钙信号。具体目标是：（i）表征门控和Ca2 + 渗透性能的IP3R，并开发了预测数学模型，以解释其复杂的 通过IP3和Ca2+的调节;（ii）观察和模拟随机的，Ca2+介导的功能耦合之间的 集群内的单个通道，以及;（iii）确定集群间相互作用的机制 这使得全球信号的传播和Ca2+对这一过程的强大差异调制成为可能 不同动力学的缓冲液。我们专注于单个实验易处理系统（人类SH-）中的IP 3信号传导 SY5Y神经母细胞瘤细胞），但我们开发的实验和理论工具将广泛适用， 这些涌现原理将阐明许多细胞类型中Ca2+信号传导的基本机制。我们 小组包括五名首席研究员，其专业知识和职责如下： 约翰·皮尔森洛斯阿拉莫斯理论家-提供总体方向和数据综合; 低维IP3受体模型和综合多尺度细胞模型的构建。 Kevin Foskett和丹尼尔Mak U。宾夕法尼亚州实验学家-电生理单通道 记录和IP3受体/通道建模。 伊恩帕克。U.C.欧文实验学家-胞质钙成像和建模。 帅建威。厦门大学理论家。Ca2+信号的计算机建模。 我们的研究结果将有助于阐明复杂的钙信号调节正常细胞的机制。 身体中几乎所有细胞的功能，其破坏与多种疾病有关， 老年痴呆症躁郁症和心力衰竭。

ABSTRACT The overall goal of this project involves a synergistic approach of multi-scale modeling and experimental observation to elucidate the fundamental mechanisms underlying cellular calcium signaling. Cytosolic Ca2+ transients serve as a ubiquitous signaling mechanism that regulates cellular functions as diverse as secretion, contraction and proliferation. Information is encoded by spatio-temporal patterns of cytosolic Ca2+ signals at scales ranging from nanometers and microseconds to millimeters and minutes, involving `phonemes' of Ca2+ constructed hierarchically through the activity of individual channels; multiple channels within clusters; and interactions between clusters. These levels cannot simultaneously be observed by any single experimental technique and the shorter scales are below experimental resolution. We therefore employ a dual, tightly integrated and iterative approach of data-driven mathematical modeling together with experimental measurements involving electrophysiological single-channel recording and high-resolution cellular Ca2+ imaging to elucidate how 'elementary' Ca2+ events involving individual channels and clusters are triggered and coupled to produce global cellular calcium signals. Specific aims are to: (i) characterize the gating and Ca2+ permeation properties of IP3R, and develop a predictive mathematical model to account for its complex regulation by IP3 and Ca2+; (ii) observe and model the stochastic, Ca2+-mediated functional coupling between individual channels within a cluster, and; (iii) determine the mechanisms underlying cluster-cluster interactions that allow for propagation of global signals and the powerful differential modulation of this process by Ca2+ buffers of differing kinetics. We focus on IP3 signaling in a single experimentally-tractable system (human SH- SY5Y neuroblastoma cells), but the experimental and theoretical tools we develop will be widely applicable, and the emergent principles will illuminate fundamental mechanisms of Ca2+ signaling in many cell types. Our group involves five Lead Investigators, with expertise and responsibilities as follows: John Pearson. Los Alamos. Theoretician - provides overall direction and synthesis of data; construction of low-dimensional IP3 receptor model and comprehensive multi-scale cellular models. Kevin Foskett and Daniel Mak U. Penn. Experimentalists - electrophysiological single-channel recording and IP3 receptor/channel modeling. Ian Parker. U.C. Irvine. Experimentalist - cytosolic Ca2+ imaging and modeling. Jianwei Shuai. Xiamen University. Theoretician. Computer modeling of Ca2+ signals. Our results will help elucidate the mechanisms underlying complex calcium signals that regulate the normal functioning of almost all cells in the body, and whose disruption is implicated in diseases as diverse as Alzheimers, bipolar disorder, and heart failure.