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

脉动胰岛素分泌驱动的生化系统的多尺度建模、模拟和敏感性分析

• 批准号: 0726763
• 负责人: Yang Cao
• 金额: $ 25万
• 依托单位: Virginia Polytechnic Institute and State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0726763&HistoricalAwards=false
• 关键词: Multiscale; Modeling; Simulation; Sensivitity; Analysis

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.

本研究从不同的尺度，从单个线粒体到多个线粒体之间的耦合，探讨了与糖尿病胰岛素分泌缺陷直接相关的线粒体驱动的钙离子和细胞内ATP/ADP的耦合振荡机制。从单个细胞中的多个（100至200个）线粒体到单个胰岛中的多个（1，000至10，000个）细胞之间的偶联。 在初步开发了一个严格的多尺度建模和仿真的数学建模框架，该框架被应用于开发一个模型的振荡机制，在一个单一的振荡器。 然后，这些模型耦合在一起，使用空间信息来表示多个线粒体和耦合振荡在一个单一的细胞。 最后，采用大规模并行计算模拟单个胰岛内多个细胞之间的耦合振荡。 该项目严格测试了所有尺度的振荡同步对于胰岛素的正确分泌是必要的这一假设。