Cytoskeletal Oscillations: Mathematical Modeling Integrated with Experiments

细胞骨架振荡：数学建模与实验相结合

• 批准号: 7404449
• 负责人: Timothy C Elston
• 金额: $ 31.19万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7404449
• 关键词: Actomyosin; Affect; Automobile Driving; Behavior; Biochemical; Biochemistry; Biological; Biological Process; Biophysics; Cardiac Myocytes; Cells; Cellular biology; Cereals; Chemicals; Complex; Coupling; Cytoskeleton; Data; Elements; Equation; Etiology; Eukaryotic Cell; Generations; Goals; Hand; Heterogeneity; Interdisciplinary Study; Light; Maps; Measures; Mechanics; Membrane; Methods; Microscopic; Modeling; Molecular; Motor; Numbers; Pathway interactions; Research; Role; System; Techniques; Testing; Time; Uncertainty; base; cell motility; cell transformation; cell type; design; experience; mathematical model; novel; physical model; programs; research study; theories; tool

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?

描述（由申请人提供）：在细胞和分子水平上发生的生物过程由大量相互作用的元素组成，是高度非线性的，并且通常涉及多个时间和空间尺度。这些系统的定量描述非常重要，但也提出了巨大的挑战。不同的数学技术将不同程度的生物学细节纳入系统的描述中。适当的建模方法由驱动生物学问题决定。我们建议开发和分析不同复杂度的数学模型，以了解扩散细胞中的收缩性振荡现象。 基于肌动球蛋白的皮质收缩性是真核细胞的共同特征，但仅在少数细胞类型（例如心肌细胞）中发现产生节律性收缩的能力。细胞在平滑、单调状态和脉动状态之间转换的机制尚不清楚。这些振荡由复杂的机械化学系统控制。我们的建模工作将与旨在通过实验测量模型参数和测试模型预测的实验程序完全集成。根据数据的保证，模型的机械细节将会增加。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，以充分描述所观察到的振荡行为背后的机械化学耦合。将开发和验证一种新颖的粗粒度方法（c-map），旨在捕获系统的定性特征。一方面，该工具将成为实验和物理建模之间的中间体，确定主要的必要元素、它们的相互作用以及因果关系传播的路径。另一方面，c-map将作为独立的工具来探索单元的层次组织以及不确定性在系统中的作用。 该项目有三个具体目标：1）在扩散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成分和力学联系起来？细胞元素的空间异质性如何影响振荡？