Electrical And Chemical Oscillations In Coupled Cell Sys

耦合电池系统中的电气和化学振荡

• 批准号: 6532080
• 负责人: Arthur Stewart Sherman
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6532080
• 关键词: Langerhans' cell; biophysics; calcium channel; cell cell interaction; electrophysiology; gonadotropin releasing factor; insulin; intracellular; mathematical model; membrane activity; membrane channels; membrane model; membrane potentials; model design /development; neurons; neurotransmitters; pancreatic islet function; pancreatic islets; secretion; synapses

We use mathematical models to study the mechanisms of oscillatory electrical activity arising from ion channels in cell membranes and modulated by intracellular chemical processes. We are interested in both the behavior of single cells and the ways in which cells communicate and modify each other's behavior. Our main application has been to the biophysical basis of insulin secretion in pancreatic beta-cells. We have examined bursting oscillations in membrane potential and the role of electrical coupling between cells in the islet of Langerhans. Long term goals are to understand how the membrane dynamics interact with intracellular events to regulate secretion. We also compare, contrast, and generalize to other secretory cells and neurons, including GnRH-secreting hypothalamic neurons, pituitary somatotrophs, and fast neurotransmitter secretion at nerve terminals. Our primary tool is the numerical solution of ordinary and partial differential equations. We use analytical, geometrical, graphical, and numerical techniques from the mathematical theory of dynamical systems to help construct and interpret the models. Perturbation techniques are used to get analytical results in special cases. We study both detailed biophysical models and simplified models which are more amenable to analysis. Such an approach aids the isolation of the essential or minimal mechanisms underlying phenomena, the search for general principles, and the application of concepts and analogies from other fields. We see a role for our group as intermediaries between the mathematical and biological disciplines. This includes disseminating the insights of mathematical work to biologists in accessible language and alerting mathematicians and other theoreticians to new and challenging problems arising from biological issues. Recent work on this project includes: 1. We developed a model to account for the wide range of oscillation periods for membrane potential and calcium observed in pancreatic beta-cells and islets (from seconds to minutes). The hypothesis was that oscillations are governed by two slow, negative feedback processes, one with a time constant of 1-5 seconds, and one with a time constant of 2 minutes. There is no process with an intermediate time constant - oscillations in that range result from the interaction between the two faster and slower processes. In collaboration with the Satin lab we confirmed a key prediction of the model that appropriate injected currents could elicit medium-scale oscillations from fast cells. This showed for the first time that isolated cells from pancreatic islets could indeed exhibit medium oscillations (Ref. #1). 2. We have studied how electrical coupling of pancreatic beta-cells contributes to medium-scale (10-60 sec) bursting oscillations in calcium and membrane potential observed in pancreatic islets. We focused on the sub-group (30 - 50%) of isolated cells identified by the Satin lab that show rapid and continuous spiking rather than bursts of spikes. We had previously shown that such cells, when electrically coupled, could be transformed into bursters. However, the phenomenon was not robust, existing only for a small range of coupling strengths. We have now shown and analyzed mathematically that nonlinear effects of stochastic ion channel fluctuations (Ref. # 2) and heterogeneity of parameters (Ref. # 3) can enhance this form of emergent bursting. This study provides an interesting contrast and complement to our previous demonstrations that noise and heterogeneity hinder bursting when added to cells that are intrinsic bursters when uncoupled. 3. We have extended our previous studies of store-operated calcium channels (SOC) in pancreatic beta-cells to neuro-endocrine cells of the hypothalamus that secrete GnRH. In collaboration with the Stojilkovic lab, we showed that SOC could account for the increased action potential frequency and increased cytosolic calcium levels seen when the cells are stimulated with GnRH (the cells have autoreceptors for their own secretion product). See Refs. # 4 and 6. 4. We have carried out a detailed mathematical analysis of the steady-state spatial profile of calcium near an open calcium channel and how it is modified by calcium buffers. This resulted in a systematic and unified treatment of several approximate formulas previously obtained by others using heuristic arguments. Such a treatment also indicates in which parameter regimes the various approximations are valid and leads to refined approximations that are more accurate, provided they are used in the appropriate parameter regimes. See Ref. #5.

我们使用数学模型来研究振荡电活动的机制所产生的离子通道在细胞膜和细胞内的化学过程调制。我们感兴趣的是单细胞的行为和细胞之间的通信方式，并修改彼此的行为。我们的主要应用是胰腺β细胞胰岛素分泌的生物物理基础。我们已经研究了膜电位的爆发振荡和胰岛细胞之间的电耦合的作用。长期目标是了解膜动力学如何与细胞内事件相互作用以调节分泌。我们也比较，对比，并概括到其他分泌细胞和神经元，包括GnRH分泌下丘脑神经元，垂体生长激素细胞，和快速神经递质分泌的神经末梢。我们的主要工具是常微分方程和偏微分方程的数值解。我们使用动力系统数学理论中的分析、几何、图形和数值技术来帮助构建和解释模型。在特殊情况下，利用摄动技术得到了解析结果。我们研究了详细的生物物理模型和简化的模型，更适合分析。这种方法有助于分离现象背后的基本或最低限度的机制，寻找一般原则，并应用其他领域的概念和类比。我们看到了我们小组作为数学和生物学科之间的中介的作用。这包括传播的见解数学工作的生物学家在可访问的语言和提醒数学家和其他理论家的新的和具有挑战性的问题所产生的生物问题。该项目的近期工作包括：1。我们开发了一个模型来解释在胰腺β细胞和胰岛中观察到的膜电位和钙的振荡周期的宽范围（从秒到分钟）。假设振荡是由两个缓慢的负反馈过程控制的，一个时间常数为1-5秒，另一个时间常数为2分钟。不存在具有中间时间常数的过程--在该范围内的振荡是由两个较快和较慢过程之间的相互作用引起的。在与Satin实验室的合作中，我们证实了模型的一个关键预测，即适当的注入电流可以引起快细胞的中等规模振荡。这第一次表明，从胰岛分离的细胞确实可以表现出中等振荡（参考文献#1）。2.我们已经研究了胰腺β细胞的电耦合如何有助于在胰岛中观察到的钙和膜电位的中等规模（10-60秒）爆发振荡。我们专注于Satin实验室鉴定的分离细胞的亚组（30 - 50%），这些细胞显示快速和连续的尖峰，而不是尖峰的爆发。我们之前已经证明，这种细胞，当电耦合，可以转化为爆发。然而，该现象并不稳健，仅存在于小范围的耦合强度。我们现在已经用数学方法证明并分析了随机离子通道波动（参考文献2）和参数异质性（参考文献3）的非线性效应可以增强这种形式的涌现爆发。这项研究提供了一个有趣的对比和补充，我们以前的演示，噪音和异质性阻碍爆裂时，加入到细胞的内在爆发时，解偶联。3.我们已经将我们先前对胰腺β细胞中钙库操纵的钙通道（SOC）的研究扩展到分泌GnRH的下丘脑神经内分泌细胞。在与Stojilkovic实验室的合作中，我们发现SOC可以解释当细胞被GnRH刺激时观察到的动作电位频率增加和细胞溶质钙水平增加（细胞具有自身分泌产物的自受体）。参见参考文献。#4和6。4.我们已经进行了详细的数学分析的稳态空间分布的钙附近的开放的钙通道，以及它是如何修改的钙缓冲液。这导致了一个系统和统一的治疗几个近似公式以前获得他人使用启发式参数。这样的处理还指示在哪些参数机制中各种近似是有效的，并且导致更精确的精炼近似，只要它们在适当的参数机制中使用。参见参考文献5。