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

本研究从不同尺度，从单个线粒体，到单个细胞(100~200个)线粒体之间的耦合，再到单个胰岛(1,000~10,000个)细胞之间的耦合，研究了线粒体驱动细胞内钙离子和细胞内ATP/ADP耦合的机制，这与胰岛素分泌的脉动性缺陷有直接关系。在初步开发了用于多尺度建模和仿真的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的振荡机制的模型。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，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。这个项目严格测试了这样一种假设，即所有尺度上的振荡同步对于正确的胰岛素分泌是必要的。

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.