RAPID: Multiscale Modeling Of SARS-CoV-2 Viral Intracellular and Intercellular Dynamics

__在短短几周内引起了全球性的反响。地球仪将在相当长的一段时间内感受到巨大的社会、经济和健康负面影响。必须采取许多补充战略来解决这一问题并减轻其后果。显然需要采取的一项战略是更好地了解SARS-CoV-2的基本生物学。该项目的目标是创建SARS-CoV-2病毒细胞内和细胞间病毒动力学的多尺度模型。使用系统病毒学方法。该项目将提供对病毒如何工作的理解，并将为许多基础研究和开发有效药物和疗法的应用工作提供必要的框架。开发的模型将在开源许可证下发布，并从GitHub网站免费提供。该项目将在计算系统病毒学领域培训一名研究生。该项目基于目前对病毒反应网络的理解，创建了SARS-2019-CoV-2病毒的细胞内和细胞间模型。利用反应动力学理论，将反应网络拓扑转化为数学模型。一组常微分方程描述感染细胞内的病毒复制的动力学制定与使用的质量作用动力学范式。通过对模型参数空间的Monte Carlo抽样，以及灵敏度分析和稳定性分析，确定了数学和生物约束。进行随机模拟以确定是否存在具有潜在不同表型的感染细胞亚群。最后，使用的基本演算的原则接地，细胞内模型耦合到一个标准的细胞间模型的病毒复制动力学。多尺度模型进行相同的分析，细胞内模型，也实施随机，以确定是否纳入更高的尺度信息影响预测的亚群distribution.This奖项反映了NSF的法定使命，并已被认为是值得支持的，通过评估使用基金会的智力价值和更广泛的影响审查标准。

________________________________________________________________________________________________________________The recent emergence of the SARS-CoV-2 virus, the etiological agent of COVID-19, has caused worldwide repercussions in just a few short weeks. The tremendous negative social, economic and health impact will be felt for a considerable time around the globe. Numerous complementary strategies must be taken to address this issue and to ameliorate the consequences. One such strategy that is clearly required is a better understanding of the fundamental biology of SARS-CoV-2. The objective of this project is to create a multiscale model of the intracellular and intercellular viral dynamics of the SARS-CoV-2 virus. A systems virology approach is used. This project would deliver an understanding of how the virus works and will provide the framework necessary for numerous fundamental studies and applied efforts for developing effective drugs and therapies. The developed model would be released under an open source license and made freely available from the GitHub website. The project would train one graduate student in the area of computational systems virology. This project creates intracellular and intercellular models of the SARS-2019-CoV-2 virus based on the current understanding of the virus reaction network. The reaction network topology is translated into a mathematical model with the use of the theory of reaction kinetics. A set of ordinary differential equations describing the dynamics of viral replication within an infected cell is formulated with the use of the mass action kinetics paradigm. With the use of Monte Carlo sampling of the model’s parameter space, as well as sensitivity analysis and stability analysis, mathematical and biological constraints are identified. Stochastic simulation is carried out to determine whether subpopulations of infected cells exist with potentially different phenotypes. Finally, with the use of principles grounded in basic calculus, the intracellular model is coupled to a standard intercellular model of viral replication dynamics. The multiscale models undergo the same analyses as the intracellular model and is also implemented stochastically to determine if incorporating higher scale information influences prediction of subpopulation distribution.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.