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

本研究探讨了线粒体驱动的钙离子与细胞ATP/ADP耦合振荡的机制，这与搏动性胰岛素分泌缺陷有直接关系。振荡机制在不同的尺度上进行了研究，从单个线粒体到单个细胞中多个（100到200）线粒体之间的偶联，再到单个胰岛中多个（1000到10000）细胞之间的偶联。在最初为多尺度建模和模拟开发了严格的数学建模框架之后，该框架被应用于开发单个线粒体振荡机制的模型。然后使用空间信息将这些模型耦合在一起，以表示单个细胞中的多个线粒体和耦合振荡。最后，利用大规模并行计算模拟了单个胰岛内多个细胞之间的耦合振荡。该项目严格检验了在所有尺度上振荡同步是胰岛素正确分泌所必需的假设。

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.