Multi-timescale Analysis of Cellular Electrical Activity

细胞电活动的多时间尺度分析

• 批准号: 1853342
• 负责人: Richard Bertram
• 金额: $ 36.94万
• 依托单位: Florida State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1853342&HistoricalAwards=false
• 关键词: Multi; timescale; Analysis; Cellular; Electrical

This project will use mathematical and computational analysis to understand patterns of activity in hormone-secreting endocrine and cardiac cells. Numerous cells in the body are electrically active. They produce electrical impulses, and these impulses through which nerve cells code and transmit information, endocrine cells secrete hormones, and muscle cells initiate contraction. Understanding the electrical activity of these cells is fundamental to understanding their behavior. This is, no easy task, since the electrical activity is mediated by ion flow through several types of ion channels in the cell membrane interacting in nonlinear ways through the membrane potential. Adding to this complexity, there are numerous intracellular signaling molecules acting on some of these channels and modifying their behavior. This project focuses on oscillations in the membrane potential of insulin-secreting cells of the pancreas, stress-hormone-secreting pituitary cells, and cells of the cardiac ventricles. These oscillations can be beneficial or pathological, depending on the cell type. One objective of this project is to understand why the oscillations happen and, in the case that they are pathological, to determine how they can be terminated. Another objective is to train undergraduate and graduate students in the theory and application of sophisticated mathematical techniques that are directly applicable to biological systems. This training is facilitated through the interaction with several experimental labs.The variables that describe an electrically excitable cell often vary on significantly different times scales. Some variables adapt quickly to changes in the cell's membrane potential, while others adapt more slowly. In such cases, oscillations in the membrane potential can occur at the level of the subsystem of fast variables, or at the level of the slow subsystem, or at some intermediate level that involves variables from both subsystems. To understand the basis of the oscillations, system variables should be partitioned in an appropriate way, facilitating the use of geometric singular perturbation analysis, or fast/slow analysis. This project employs fast/slow analysis in the examination of bursting oscillations in pituitary corticotrophs and pancreatic beta-cells, and pathological early after depolarizations (EADs) in ventricular myocytes. The former drive the secretion of hormones, while the latter can lead to, at the tissue level, ventricular tachycardia. The fast/slow analysis of the different models will uncover the mechanisms through which modulators of cell behavior, such as corticosteroids or glucose or hypokalemia, act to move the cell among distinct behaviors, some rhythmic and some not. It will also be used to understand the effects of different stimulus frequencies on EAD production in ventricular myocytes, which normally receive periodic stimulation from the sinoatrial node in situ. This project is supported by both Division of Mathematical Sciences/Mathematical Biology and Molecular and Cellular Biology/Cellular Dynamics and Function programs.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该项目将使用数学和计算分析来了解激素分泌内分泌细胞和心肌细胞的活动模式。体内的许多细胞都具有电活性。它们产生电脉冲，神经细胞通过这些脉冲编码和传输信息，内分泌细胞分泌激素，肌肉细胞启动收缩。了解这些细胞的电活动对于了解它们的行为至关重要。这并不是一件容易的事，因为电活动是由离子流介导的，离子流通过细胞膜中几种类型的离子通道，通过膜电位以非线性方式相互作用。更复杂的是，有许多细胞内信号分子作用于其中一些通道​​并改变它们的行为。该项目的重点是胰腺胰岛素分泌细胞、应激激素分泌垂体细胞和心室细胞膜电位的振荡。这些振荡可能是有益的，也可能是病理性的，具体取决于细胞类型。该项目的目标之一是了解振荡发生的原因，并在振荡是病态的情况下确定如何终止振荡。另一个目标是培养本科生和研究生直接适用于生物系统的复杂数学技术的理论和应用。这种训练是通过与几个实验实验室的互动来促进的。描述可电兴奋细胞的变量通常在显着不同的时间尺度上变化。一些变量能够快速适应细胞膜电位的变化，而另一些变量则适应得更慢。在这种情况下，膜电位的振荡可能发生在快速变量子系统的水平，或慢速子系统的水平，或涉及来自两个子系统的变量的某个中间水平。为了了解振荡的基础，应以适当的方式划分系统变量，以便于使用几何奇异扰动分析或快/慢分析。该项目采用快/慢分析来检查垂体促肾上腺皮质激素和胰腺 β 细胞的爆发振荡，以及心室肌细胞去极化后早期的病理性 (EAD)。 前者驱动激素的分泌，而后者可在组织水平上导致室性心动过速。对不同模型的快速/慢速分析将揭示细胞行为调节剂（例如皮质类固醇或葡萄糖或低钾血症）使细胞在不同行为之间移动的机制，有些是有节奏的，有些是无节奏的。它还将用于了解不同刺激频率对心室肌细胞 EAD 产生的影响，心室肌细胞通常在原位接受来自窦房结的周期性刺激。该项目得到了数学科学/数学生物学和分子与细胞生物学/细胞动力学和功能项目的支持。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Chronic stress facilitates bursting electrical activity in pituitary corticotrophs

慢性压力促进垂体促肾上腺皮质细胞的电活动爆发

• DOI: 10.1113/jp282367
• 发表时间: 2022-01
• 期刊: The Journal of Physiology
• 作者: Duncan, Peter J.;Fazli, Mehran;Romanò, Nicola;Le Tissier, Paul;Bertram, Richard;Shipston, Michael J.
• 通讯作者: Shipston, Michael J.

Multi-mode attractors and spatio-temporal canards

多模吸引子和时空鸭翼

• DOI: 10.1016/j.physd.2020.132544
• 发表时间: 2020-10
• 期刊: Physica D: Nonlinear Phenomena
• 作者: Vo, Theodore;Bertram, Richard;Kaper, Tasso J.
• 通讯作者: Kaper, Tasso J.

Chronic stimulation induces adaptive potassium channel activity that restores calcium oscillations in pancreatic islets in vitro

慢性刺激诱导适应性钾通道活性，在体外恢复胰岛中的钙振荡

• DOI: 10.1152/ajpendo.00482.2019
• 发表时间: 2020-04
• 期刊: American Journal of Physiology-Endocrinology and Metabolism
• 影响因子: 5.1
• 作者: Law, Nathan C.;Marinelli, Isabella;Bertram, Richard;Corbin, Kathryn L.;Schildmeyer, Cara;Nunemaker, Craig S.
• 通讯作者: Nunemaker, Craig S.

Pulsatile Basal Insulin Secretion Is Driven by Glycolytic Oscillations

脉动基础胰岛素分泌是由糖酵解振荡驱动的

• DOI: 10.1152/physiol.00044.2021
• 发表时间: 2022-07
• 期刊: Physiology
• 影响因子: 8.4
• 作者: Fletcher, P. A.;Marinelli, I.;Bertram, R.;Satin, L. S.;Sherman, A. S.
• 通讯作者: Sherman, A. S.

A closed-loop multi-scale model for intrinsic frequency-dependent regulation of axonal growth

用于轴突生长的内在频率依赖性调节的闭环多尺度模型

• DOI: 10.1016/j.mbs.2021.108768
• 发表时间: 2022-02
• 期刊: Mathematical Biosciences
• 影响因子: 4.3
• 作者: Bai, Fan;Bertram, Richard;Karamched, Bhargav R.
• 通讯作者: Karamched, Bhargav R.