Cytoskeletal Oscillations: Mathematical Modeling Integrated with Experiments

描述(申请人提供)：发生在细胞和分子水平的生物过程由大量相互作用的元素组成，是高度非线性的，通常涉及多个时间和空间尺度。对这些系统的定量描述非常重要，但也面临着巨大的挑战。不同的数学技术将不同程度的生物学细节结合到系统的描述中。适当的建模方法是由驾驶生物学问题决定的。我们建议建立和分析不同复杂性的数学模型，以理解扩展细胞中的收缩振荡现象。 基于肌动球蛋白的皮质收缩能力是真核细胞的共同特征，但只有少数类型的细胞才能产生节律性收缩，如心肌细胞。细胞在光滑、单调状态和脉动状态之间转换的机制尚不清楚。这些振荡是由一个复杂的机械力-化学系统控制的。我们的建模工作将与一个实验程序完全集成，该程序旨在通过实验测量模型参数并测试模型预测。模型的机械细节将根据数据的保证而增加。建模方法将包括日益复杂的常微分方程模型和空间扩展模型，这些模型完全描述了作为所观察到的振荡行为的基础的机械化学耦合。将开发和验证一种新的过程粒度方法(c-map)，旨在捕捉系统的质量特征。一方面，这个工具将是实验和物理模型之间的中介，确定主要的必要元素、它们的相互作用和因果关系传播的路径。另一方面，c-map将作为一个独立的工具来探索细胞的层次组织和不确定因素在系统中的作用。 该项目有三个具体目标：1)在传播细胞中产生振荡的基本必要元素是什么？2)细胞的各种外部机械力化学输入如何影响振荡行为？3)生化网络如何与细胞骨架的组成和机制相连，以及细胞元素的空间异质性如何影响振荡？

DESCRIPTION (provided by applicant): Biological processes that occur at the cellular and molecular level consist of large numbers of interacting elements, are highly nonlinear and generally involve multiple time and spatial scales. The quantitative description of these systems is of great importance but presents large challenges. Different mathematical techniques incorporate varying levels of biological detail into the description of the system. The appropriate modeling approach is dictated by the driving biological problem. We propose to develop and analyze mathematical models of varying complexity to understand the phenomenon of contractility oscillations in spreading cells. Actomyosin-based cortical contractility is a common feature of eukaryotic cells, but the capability to produce rhythmic contractions is found in only a few cell types such as cardiomyocytes. The mechanisms by which cells transform between smooth, monotonic states and pulsatile states is not understood. These oscillations are governed by a complex mechano-chemical system. Our modeling effort will be fully integrated with an experimental program designed to experimentally measure parameters for the models and test model predictions. The mechanistic details of the models will increase as warranted by the data. The modeling methods will include increasingly complex ordinary differential equation models and spatially-extended models that fully describe the mechonchemical coupling that underlies the observed oscillatory behavior. A a novel course-grained approach (c-map) designed to capture qualitative features of the system, will be developed and validated. This tool, on one hand, will be an intermediate between experiments and physical modeling, determining major requisite elements, their interactions and paths of causality propagation. On the other hand, the c-map will be used as an independent tool to explore the hierarchical organization of cell and the role of uncertainties in the system. The project has three specific aims: 1) What are the basic necessary elements for generation of oscillations in spreading cells? 2) How do various external mechanochemical inputs to the cell affect oscillatory behavior? 3) How is the biochemical network connected to the constituents and mechanics of the cytoskeleton and how does spatial heterogeneity of cellular elements affect the oscillations?