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: 6983597
• 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/6983597
• 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. (Role of the Endoplasmic Reticulum in Shaping Calcium Oscillations) We have shown that adding a simple ER with only linear uptake and release mechanisms is sufficient to account for most features of cytosolic Ca2+ kinetics, provided the ER is much slower than cytosolic Ca2+, but not too slow. It must be able to fill and empty substantially during a burst cycle (tens to hundreds of seconds) in order to impart its slow kinetics to cytosolic Ca2+. 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 in addition simulation of the triphasic transient response of islets to a step of glucose (latency, first phase spiking, and steady-state oscillation). See Bertram and Sherman (2004). Not all additional mechanisms are helpful, however. We have found that including active calcium-induced calcium release (CICR) results in an ER that does not fill and empty in response to cytosolic calcium oscillations and fails to account for the increase in the amplitude of cytosolic calcium transients when ER uptake is blocked. A paper is in press. 2. (Electrical Coupling and Emergent Oscillations in Pancreatic Islets) We have extended our work on how the heterogeneous properties of islet beta-cells contributes to the collective behavior of intact islets. Using the phantom bursting model mentioned above (Bertram and Sherman, 2004), we have shown that coupling fast and slow cells can produce the intermediate period electrical oscillations typically seen in islets. This is not very surprising, but we found further that a bimodal distribution of single-cell periods could be generated with a unimodal distribution of channel conductances. It is also possible to construct islets consisting of only fast cells or only slow cells that exhibit intermediate period oscillations when coupled. See Zimliki et al (2004). 3. (Combined Electrical and Metabolic Oscillations in Pancreatic Islets) Although electrical osscillations in pancreatic islets are important for understanding many phenomena, their properties are at variance with observations of pulsatile insulin secretion in vivo. We have proposed that this can be explained by the modulation of the electrical oscillations by metabolic (glycolytic) oscillations. In particular, this combination can account for the observations of compound oscillations (bursts of bursts) that have been observed in membrane potential, cytosolic calcium, and metabolic variables such as intra-islet oxygen and glucose and mitochondrial membrane potential. We suggest that the glycolytic oscillations maintain optimal timing to coordinate insulin secretion and insulin action while the electrical oscillations control the quantity of insulin secreted in each pulse. See Bertram et al (2004).

我们使用数学模型来研究由细胞膜离子通道引起并受细胞内化学过程调节的振荡电活动的机制。我们对单个细胞的行为以及细胞沟通和修改彼此行为的方式感兴趣。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。我们研究了膜电位的爆发振荡以及朗格汉斯岛细胞之间电耦合的作用。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。我们还比较、对比和推广其他分泌细胞和神经元，包括分泌 GnRH 的下丘脑神经元、垂体生长激素细胞和神经末梢的快速神经递质分泌。 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。扰动技术用于在特殊情况下获得分析结果。我们研究详细的生物物理模型和更易于分析的简化模型。这种方法有助于分离现象背后的基本或最小机制、寻找一般原理以及应用其他领域的概念和类比。我们小组的另一个角色是在数学和生物学科之间进行协调。这包括以易于理解的语言向生物学家传播数学工作的见解，并提醒数学家和其他理论家注意生物学问题引起的新的和具有挑战性的问题。 该项目最近的工作包括： 1.（内质网在塑造钙振荡中的作用） 我们已经证明，添加仅具有线性摄取和释放机制的简单 ER 足以解释细胞溶质 Ca2+ 动力学的大多数特征，前提是 ER 比细胞溶质 Ca2+ 慢得多，但不是太慢。它必须能够在爆发周期（数十至数百秒）内充分填充和排空，以便将其缓慢的动力学传递给胞质 Ca2+。 包含内质网动力学足以解释胰岛素分泌增强剂乙酰胆碱存在下爆发频率的增加。包含核苷酸比率动力学还允许模拟胰岛对葡萄糖步骤的三相瞬态响应（潜伏期、第一相尖峰和稳态振荡）。参见 Bertram 和 Sherman (2004)。 然而，并非所有附加机制都有帮助。我们发现，包括活性钙诱导的钙释放（CICR）会导致内质网不会响应细胞质钙振荡而填充和排空，并且无法解释当内质网摄取受阻时细胞质钙瞬变幅度的增加。一篇论文正在印刷中。 2.（胰岛中的电耦合和突发振荡）我们扩展了关于胰岛β细胞的异质特性如何影响完整胰岛的集体行为的工作。使用上面提到的幻影爆发模型（Bertram 和 Sherman，2004），我们已经证明快速和慢速细胞的耦合可以产生通常在胰岛中看到的中间周期电振荡。这并不奇怪，但我们进一步发现单细胞周期的双峰分布可以通过通道电导的单峰分布产生。还可以构建仅由快细胞或仅由慢细胞组成的胰岛，这些胰岛在耦合时表现出中间周期振荡。参见 Zimliki 等人 (2004)。 3.（胰岛中的电振荡和代谢振荡相结合）尽管胰岛中的电振荡对于理解许多现象很重要，但它们的特性与体内脉动胰岛素分泌的观察结果不一致。我们提出这可以通过代谢（糖酵解）振荡对电振荡的调节来解释。特别是，这种组合可以解释在膜电位、胞质钙和代谢变量（例如胰岛内氧和葡萄糖以及线粒体膜电位）中观察到的复合振荡（爆发的爆发）。我们建议糖酵解振荡保持最佳时机来协调胰岛素分泌和胰岛素作用，而电振荡控制每个脉冲中分泌的胰岛素数量。参见 Bertram 等人 (2004)。