Spatio-Temporal Dynamics of Cell Calcium

细胞钙的时空动态

• 批准号: 1517085
• 负责人: Victor Matveev
• 金额: $ 20万
• 依托单位: New Jersey Institute of Technology
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1517085&HistoricalAwards=false
• 关键词: Spatio; Temporal; Dynamics; Cell; Calcium

Calcium-dependent synaptic neurotransmitter release is the primary means of communication between neurons in the central and peripheral nervous systems, including the mammalian brain. It is triggered by the entry of calcium ions into the cell, followed by their diffusion and binding to calcium-sensing proteins. This fundamental physiological cell process is called secretory vesicle exocytosis, and is also responsible for neuro-muscular communication and the release of hormone from endocrine cells. Accurate modeling and deeper understanding of cell calcium signals that trigger neurotransmitter release and endocrine hormone release is at the core of the current project, and may provide deeper insight into the function of neural and endocrine systems both in the normal state and in pathological conditions, for instance type-II diabetes. This project will employ advanced mathematical and computational techniques in order to gain deeper knowledge of physiologically relevant cell calcium dynamics with high resolution in time and space. This will include further development of an open-source computational tool called CalC ("Calcium Calculator") for the simulation of three-dimensional cell calcium ion diffusion and calcium binding (http://www.calciumcalculator.org), contributing to the infrastructure for computational modeling in the biological sciences, facilitating rapid and effective dissemination of the obtained results through the publicly accessible on-line simulation file database. Students will be trained in the highly interdisciplinary field spanning applied mathematics, cell biophysics and computational neuroscience, contributing to the development of future researchers capable of using advanced computational methods to tackle problems of broad societal impact in the life sciences.This project addresses several challenges in the modeling of cell calcium dynamics leading to neurotransmitter and hormone release. One of these challenges is taking into account the strong influence of various intracellular calcium-binding molecules, collectively termed calcium buffers and sensors, on cell calcium diffusion. This project extends recent studies of calcium diffusion in the presence of buffers with several calcium binding sites that bind calcium cooperatively through a mechanism similar to the process of cooperative binding of oxygen by hemoglobin. Cooperative binding distinguishes an important class of calcium buffer-sensors evolutionarily linked to calmodulin, and deeper understanding of their influence on calcium signals is important for the understanding of cell physiology.This project also explores the relationship between the two most widely used approaches in modeling calcium dynamics: the deterministic approach that models calcium as a continuous concentration distribution, and the stochastic approach that simulates trajectories of individual calcium ions and is assumed to be more realistic, but more expensive computationally. A novel analytical method will be applied to more accurately estimate stationary distribution of calcium near a single membrane calcium channel, allowing efficient modeling and analysis of calcium "nanodomains" that form around open calcium channels. Finally, through collaborative work with experimental physiologists, obtained methods and results will be applied to understand the interplay between calcium diffusion, buffering and sensing that underlies the observed dynamics of vesicle release in specific types of mammalian synapses and endocrine cells.

依赖钙的突触神经递质释放是中央和周围神经系统（包括哺乳动物脑）神经元之间通信的主要手段。它是由钙离子进入细胞的触发，然后扩散并与钙敏感蛋白结合。这种基本的生理细胞过程称为分泌囊泡胞吐作用，还负责神经肌肉通信和内分泌细胞中激素的释放。对触发神经递质释放和内分泌激素释放的细胞钙信号的准确建模和更深入的了解是当前项目的核心，并且可以更深入地深入了解正常状态和病理状态下神经和内分泌系统功能的功能，例如类型II糖尿病。该项目将采用先进的数学和计算技术，以便更深入地了解具有高分辨率的生理相关细胞钙动力学。这将包括进一步开发一种称为CALC（“钙计算器”）的开源计算工具，以模拟三维细胞钙离子扩散和钙结合（http://www.calciumcalculator.org），从而为良好的基础结构及其供应的基础结构促进生物学现象，构成构想的基础结构，并促进了构想的生物学现象，构造了构图，构成了构图，构成了构图，构造了构图的基础结构。在线仿真文件数据库。 Students will be trained in the highly interdisciplinary field spanning applied mathematics, cell biophysics and computational neuroscience, contributing to the development of future researchers capable of using advanced computational methods to tackle problems of broad societal impact in the life sciences.This project addresses several challenges in the modeling of cell calcium dynamics leading to neurotransmitter and hormone release.这些挑战之一是考虑到各种细胞内钙结合分子的强大影响，共同称为钙缓冲液和传感器对细胞钙扩散的影响。该项目扩展了在存在一些钙结合位点的缓冲液的情况下进行的钙扩散的研究，这些钙结合位点通过与血红蛋白对氧气结合过程相似的机制结合了钙。合作结合区分了一类重要的钙缓冲液传感器与钙调蛋白的进化相关，并且对它们对钙信号的影响的更深入的理解对于对细胞生理学的理解至关重要。该项目还探索了两种最广泛使用的方法，探索了对钙的建模和模型的始终浓度分布的确定性方法，并探索了始终的浓度分布，并探索了对稳定的稳定性分布的模型，该方法是对稳定量的contractium contripation contricium contricium contricium contricium contrication contricium contricatif的方法。更现实，但在计算上更昂贵。一种新型的分析方法将应用于更准确地估计单个膜钙通道附近钙的固定分布，从而可以有效建模和分析围绕开放钙通道形成的钙“纳米域”。最后，通过与实验生理学家的协作工作，将获得的方法和结果将应用于了解钙扩散，缓冲和感测之间的相互作用，这是囊泡释放的动力学源于特定类型的哺乳动物突触和内分泌细胞的动力学。