Spatio-Temporal Dynamics Of 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.