Spatio-Temporal Dynamics of Cell Calcium

钙依赖突触神经递质的释放是中枢神经系统和周围神经系统，包括哺乳动物大脑中神经元之间的主要交流方式。它是由钙离子进入细胞，然后扩散并与钙敏感蛋白结合而触发的。这一基本的生理细胞过程被称为分泌囊泡胞吐作用，也负责神经-肌肉通讯和内分泌细胞释放激素。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理解是当前项目的核心，并可能提供对神经和内分泌系统在正常状态和病理条件下的功能的更深层次的了解，例如II型糖尿病。该项目将使用先进的数学和计算技术，以便在时间和空间上以高分辨率获得与生理相关的细胞钙动力学的更深层次的知识。这将包括进一步开发一个名为CALC(“钙计算器”)的开放源码计算工具，用于模拟三维细胞钙离子扩散和钙结合(http://www.calciumcalculator.org)，)，为生物科学的计算建模基础设施作出贡献，促进通过可供公众查阅的在线模拟文件数据库快速有效地传播所获得的结果。学生将接受横跨应用数学、细胞生物物理学和计算神经科学的高度交叉领域的培训，为未来研究人员的发展做出贡献，他们能够使用先进的计算方法来解决生命科学中广泛的社会影响问题。这个项目解决了导致神经递质和激素释放的细胞钙动力学建模的几个挑战。这些挑战之一是考虑到各种细胞内钙结合分子，统称为钙缓冲器和传感器，对细胞钙扩散的强烈影响。这个项目扩展了最近关于钙扩散的研究，这些缓冲液具有几个钙结合部位，通过类似于氧与血红蛋白协同结合过程的机制协同结合钙。协同结合区分了一类重要的钙缓冲传感器，这类传感器在进化上与钙调蛋白相连，深入了解它们对钙信号的影响对于理解细胞生理学具有重要意义。本项目还探讨了钙动力学建模中两种最广泛使用的方法之间的关系：确定性方法将钙模拟为连续的浓度分布，随机方法模拟单个钙离子的轨迹，被认为更接近实际，但计算成本更高。一种新的分析方法将被应用于更准确地估计单个膜钙通道附近的钙的稳定分布，从而能够有效地对开放的钙通道周围形成的钙“纳米域”进行建模和分析。最后，通过与实验生理学家的合作，所获得的方法和结果将被用于了解钙扩散、缓冲和感知之间的相互作用，这是观察到的特定类型哺乳动物突触和内分泌细胞囊泡释放动力学的基础。

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.