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和心脏细胞中的活动模式。体内许多细胞是电活动的。它们会产生电脉冲，以及神经细胞编码并传递信息的这些脉冲，内分泌细胞分泌激素，肌肉细胞引发收缩。了解这些细胞的电活动对于理解其行为是基础。这并不容易，因为电活动是由离子流穿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的离子。除了这种复杂性外，还有许多细胞内信号分子作用在其中一些通道​​上并改变其行为。该项目的重点是胰腺分泌细胞，分泌压力激素的垂体细胞和心脏心室细胞的膜电位的振荡。根据细胞类型，这些振荡可能是有益的或有益的。该项目的一个目的是了解为什么振荡会发生，并了解它们是病态的，以确定如何终止它们。另一个目的是培训本科生和研究生在直接适用于生物系统的复杂数学技术的理论和应用中。通过与几个实验实验室的相互作用来促进这种训练。描述电气激发电池的变量通常在显着不同的时间尺度上有所不同。有些变量迅速适应了细胞膜电位的变化，而另一些变量则更慢。在这种情况下，膜电位的振荡可能发生在快速变量的子系统或慢速子系统的级别，或在涉及两个子系统变量的某些中间水平上。为了了解振荡的基础，应以适当的方式对系统变量进行分区，以促进使用几何奇异扰动分析或快速/慢分析。该项目在检查垂体皮质营养和胰腺β细胞的爆发振荡时采用快速/缓慢的分析，并在心室心肌细胞中去极化后（EADS）早期病理学。 前者驱动激素的分泌，而后者可以在组织水平上导致心室心动过速。对不同模型的快速/慢分析将发现细胞行为调节剂（例如皮质类固醇或葡萄糖或低钾血症）的机制，可动作用在不同的行为之间移动细胞，有些有节奏，有些则没有。它也将用于了解不同刺激频率对心肌细胞EAD产生的影响，这些刺激细胞通常从原位接收辛node的定期刺激。该项目得到了数学科学/数学生物学和分子和细胞生物学/细胞动力学和功能计划的支持。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子优点和更广泛的影响来通过评估来支持的。

项目成果

Symbiosis of Electrical and Metabolic Oscillations in Pancreatic β-Cells.

• DOI: 10.3389/fphys.2021.781581
• 发表时间: 2021
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Marinelli I;Fletcher PA;Sherman AS;Satin LS;Bertram R
• 通讯作者: Bertram R

Canards Underlie Both Electrical and Ca$^{2+}$-Induced Early Afterdepolarizations in a Model for Cardiac Myocytes

鸭翼是心肌细胞模型中电和 Ca$^{2 }$ 诱导的早期后除极的基础

• DOI: 10.1137/22m147757x
• 发表时间: 2022
• 期刊: SIAM Journal on Applied Dynamical Systems
• 影响因子: 2.1
• 作者: Kimrey, Joshua;Vo, Theodore;Bertram, Richard
• 通讯作者: Bertram, Richard

Slow oscillations persist in pancreatic beta cells lacking phosphofructokinase M

缺乏磷酸果糖激酶 M 的胰腺 β 细胞中持续存在缓慢振荡

• DOI: 10.1016/j.bpj.2022.01.027
• 发表时间: 2022
• 期刊: Biophysical Journal
• 影响因子: 3.4
• 作者: Marinelli, Isabella;Parekh, Vishal;Fletcher, Patrick;Thompson, Benjamin;Ren, Jinhua;Tang, Xiaoqing;Saunders, Thomas L.;Ha, Joon;Sherman, Arthur;Bertram, Richard
• 通讯作者: Bertram, Richard

Spiking and Membrane Properties of Rat Olfactory Bulb Dopamine Neurons

• DOI: 10.3389/fncel.2020.00060
• 发表时间: 2020-03-20
• 期刊: FRONTIERS IN CELLULAR NEUROSCIENCE
• 影响因子: 5.3
• 作者: Korshunov, Kirill S.;Blakemore, Laura J.;Trombley, Paul Q.
• 通讯作者: Trombley, Paul Q.

Oscillations in K(ATP) conductance drive slow calcium oscillations in pancreatic β-cells

K(ATP) 电导的振荡驱动胰腺 β 细胞中缓慢的钙振荡

• DOI: 10.1016/j.bpj.2022.03.015
• 发表时间: 2022
• 期刊: Biophysical Journal
• 影响因子: 3.4
• 作者: Marinelli, Isabella;Thompson, Benjamin M.;Parekh, Vishal S.;Fletcher, Patrick A.;Gerardo-Giorda, Luca;Sherman, Arthur S.;Satin, Leslie S.;Bertram, Richard
• 通讯作者: Bertram, Richard