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: 7581549
• 负责人: James Kevin FOSKETT
• 金额: $ 101.44万
• 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 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7581549
• 关键词: 3-Dimensional; Accounting; Affect; Alzheimer' s Disease; Behavior; Bipolar Disorder; Buffers; Calcium; Calcium Puffs; Calcium Signaling; Calcium ion; Cell Line; Cell model; Cell physiology; Cells; Collection; Complex; Computer Simulation; Coupled; Coupling; Cytosol; Data; Data Collection; Diffusion; Disease; Electron Microscopy; Electrophysiology (science); Endoplasmic Reticulum; Environment; Event; Feedback; Fluorescence Microscopy; Goals; Heart failure; Human; ITPR1 gene; Image; Individual; Inherited; Inositol; Kinetics; Lead; Ligands; Maps; Markov Chains; Measurement; Mediating; Membrane; Modeling; Neuroblastoma; Nuclear Envelope; Pancreatitis; Pattern; Physiological; Play; Principal Investigator; Process; Property; Reaction; Regulation; Research Personnel; Resolution; Role; Shapes; Signal Transduction; Site; Source; Spatial Distribution; System; Techniques; Testing; Theoretical model; Time; Universities; analytical tool; base; cell type; experience; insight; mathematical model; millimeter; multi-scale modeling; nanometer; nanoscale; optical imaging; patch clamp; public health relevance; receptor; release of sequestered calcium ion into cytoplasm; research study; response; simulation; tool

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This unique integrative approach to discover the fundamental mechanisms by which intracellular Ca2+ signals are generated will fundamentally enhance our understanding of their normal functioning and provide insights into how their disruption affects numerous diseases as varied as pancreatitis and Alzheimer's.

描述（由申请人提供）：本项目的总体目标涉及多尺度建模和实验观察的协同方法，以阐明细胞钙信号传导的基本机制。胞质Ca 2+瞬变作为一种普遍存在的信号传导机制，调节细胞功能，如分泌、收缩和增殖。信息编码的时空模式的胞质Ca 2+信号的尺度范围从纳米和微秒到毫米和分钟，涉及“音素”的Ca 2+层次结构，通过活动的个别渠道;集群内的多个渠道;和集群之间的相互作用。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，我们采用了双重的，紧密集成和迭代的方法，数据驱动的数学建模与实验测量，涉及电生理单通道记录和高分辨率细胞Ca 2+成像，以阐明如何“基本”Ca 2+事件涉及个别通道和集群被触发和耦合，以产生全球细胞钙信号。具体目标是：（i）表征IP 3R的门控和Ca 2+渗透特性，并开发预测数学模型以解释其通过IP 3和Ca 2+的复杂调节;（ii）观察和建模簇内的各个通道之间的随机的、Ca 2+介导的功能耦合，以及; ㈢确定集群的机制-簇的相互作用，使全球信号的传播和强大的差异调节这一进程的不同动力学的Ca 2+缓冲。我们专注于IP 3信号在一个单一的实验易处理的系统（人SH-SY 5 Y神经母细胞瘤细胞），但我们开发的实验和理论工具将是广泛适用的，和新兴的原则将阐明Ca 2+信号在许多细胞类型的基本机制。我们的团队包括五名首席调查员，他们的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合成;构建低维IP 3受体模型和全面的多尺度细胞模型。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IP 3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。Ca 2+信号的计算机建模。我们的研究结果将有助于阐明复杂钙信号的机制，这些信号调节体内几乎所有细胞的正常功能，并且其破坏与阿尔茨海默氏症，双相情感障碍和心力衰竭等多种疾病有关。公共卫生相关性：这种独特的综合方法来发现细胞内Ca 2+信号产生的基本机制，将从根本上增强我们对其正常功能的理解，并深入了解其破坏如何影响胰腺炎和阿尔茨海默氏症等多种疾病。