Electrical And Chemical Oscillations In Coupled Cells

耦合电池中的电气和化学振荡

• 批准号: 6809780
• 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/6809780
• 关键词: Langerhans' cell; biophysics; calcium channel; calcium flux; cell cell interaction; computer program /software; electrophysiology; gonadotropin releasing factor; insulin; intracellular; mathematical model; membrane activity; membrane channels; membrane model; membrane potentials; model design /development; 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. Another role for our group is to mediate 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. (Islet calcium and voltage oscillations) We have applied our recently developed calcium subspace model to illuminate the differences between single beta cells and islets. In particular, we showed that the detailed properties of isolated cells can be accounted for if channel noise is included in the model. The three classes of single-cell behavior we observe (spikers, fast bursters, and plateau cells) are then obtained in the model by varying calcium channel conductance. This single parameter change explains the decrease in spike amplitude, decrease in frequency, and increase in plateau fraction as one progresses through the three classes. In a complementary study, we have (with the experimental laboratory of L. Satin) contrasted two hypotheses for the role of gap junctional coupling. One possibility is that individual beta-cells are capable of islet-like oscillations, and the coupling is needed only to synchronize the oscillations. Alternatively, it may be that coupling is needed for oscillations to occur at all. We have tested this by using anti-sense mRNA for the gap junction protein connexin 43 (Cx43) to reduce coupling strength. We find that islets with reduced coupling behave like the single cells in our previous study: they show fast spiking or bursting, but not the slow bursting seen in intact islets. With R. Bertram, we have analyzed the dynamics of the current class of models, which include ER calcium dynamics and oscillatory ATP/ADP ratio. We trace the development of such models from the earliest beta-cell model, showing the contribution of each included mechanism. Inclusion of ER dynamics is sufficient to account for the increase of burst frequency in the presence of the insulin-secretion potentiator acetylcholine. Inclusion of nucleotide ratio dynamics permits for the first time simulation of the triphasic transient response of islets to a step of glucose (latency, first phase spiking, and steady-state oscillation). We have also explored a model in which negative feedback is provided not by internal calcium, but by autocrine and paracrine effects of secreted insulin. 2.(Computer modeling of calcium diffusion and buffering) We have applied our CalC ("Calcium Calculator"; http://mrb.niddk.nih.gov/matveev) software package for simulation of buffered Ca2+ diffusion in a presynaptic terminal, to explore the buffer saturation hypothesis proposed by E. Neher. This hypothesis attempts to explain short-term synaptic facilitation as a consequence of an increase in the amplitude of successive calcium spikes due to saturation of endogenous buffers. This contrasts with a model we have previously published in which a rise of the residual calcium remaining after the spikes is responsible for facilitation. The two models are not mutually exclusive, but can coexist. It is also possible that different mechanisms predominate in different types of nerve terminals. We have carried out a systematic analysis of the conditions for the two mechanisms to operate. 3. (Metabolic insulin signaling) The detailed model of metabolic insulin signaling, which we previously developed, has now appeared. The computer files are posted at http://mrb.niddk.nih.gov/sherman/insulin.html in xpp format and have also been included in a CellML repository: http://www.cellml.org/examples/repository/sedaghat_model_2002_doc.html.

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。我们小组的另一个作用是在数学和生物学科之间进行调解。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。 该项目最近的工作包括： 1.（胰岛钙和电压振荡）我们应用我们最近开发的钙子空间模型来阐明单个β细胞和胰岛之间的差异。特别是，我们发现，如果信道噪声包括在模型中，孤立的细胞的详细属性可以占。我们观察到的三种单细胞行为（尖峰，快速爆发和高原细胞），然后通过改变钙通道电导在模型中获得。这个单一参数的变化解释了尖峰幅度的降低，频率的降低，以及随着三个类别的进展而增加的平台分数。 在一项补充研究中，我们（与L。Satin）对比了间隙连接耦合作用的两种假设。一种可能性是单个β细胞能够进行胰岛样振荡，并且仅需要耦合来同步振荡。或者，可能需要耦合才能发生振荡。我们已经通过使用差距连接蛋白连接蛋白43（Cx43）的反义mRNA来降低偶联强度来测试这一点。我们发现，耦合减少的胰岛表现得像我们以前研究中的单细胞：它们显示出快速的尖峰或爆发，但不是完整胰岛中看到的缓慢爆发。 与R. Bertram，我们已经分析了目前这类模型的动力学，其中包括ER钙动力学和振荡ATP/ADP比值。我们从最早的β-细胞模型追溯这种模型的发展，显示每个包含的机制的贡献。包括ER动力学足以解释在胰岛素分泌增强剂乙酰胆碱存在下爆发频率的增加。包括核苷酸比动态允许第一次模拟的三相瞬态响应的胰岛葡萄糖的一个步骤（潜伏期，第一阶段尖峰，和稳态振荡）。 我们还探索了一种模型，其中负反馈不是由内部钙提供的，而是由分泌的胰岛素的自分泌和旁分泌效应提供的。 2.（钙扩散和缓冲的计算机模拟）我们应用我们的CalC（“Calcium Calculator”; http：//mrb.niddk.nih.gov/matveev）软件包模拟突触前末梢中缓冲的Ca 2+扩散，以探索E.内尔这一假说试图解释短期突触易化是由于内源性缓冲液饱和导致连续钙峰幅度增加的结果。这与我们以前发表的模型形成对比，在该模型中，尖峰之后剩余的残余钙的上升是促进的原因。这两种模式不是相互排斥的，而是可以共存的。也有可能不同的机制在不同类型的神经末梢中占主导地位。我们对这两个机制运作的条件进行了系统分析。 3.（代谢胰岛素信号）我们以前开发的代谢胰岛素信号的详细模型现在已经出现。这些计算机文件以xpp格式发布在http://mrb.niddk.nih.gov/sherman/insulin.html上，并且也包含在CellML存储库中： http://www.cellml.org/examples/repository/sedaghat_model_2002_doc.html。