Multiscale Modeling, Simulation, and Sensivitity Analysis of Biochemical Systems Motivated by Pulsatile Insulin Secretion

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This research addresses the mechanism of coupled oscillations in calcium ion and cellular ATP/ADP driven by mitochondria, which is directly related to the defect in pulsatile insulin secretion indiabetes.The oscillation mechanism is studied at different scales, from an individual mitochondrion, to the coupling among multiple (100 to 200) mitochondria in a single cell, to the coupling among multiple (1,000 to 10,000) cells in a single pancreatic islet. After initially developing a rigorous mathematical modeling framework for multiscale modeling and simulation, the framework is applied to develop a model for theoscillation mechanism in a single mitochondrion. These models are then coupled together using spatial information to represent multiple mitochondria and the coupled oscillation in a single cell. Finally, massively parallel computation is used to simulate the coupled oscillation among multiple cells in a single pancreatic islet. This project rigorously tests the hypothesis that synchronization of the oscillations at all scales is necessary for the correct secretion of insulin.