Mathematical Modeling and Computational Analysis of Cell and Tissue Movement

该项目的总体目标是开发一个多尺度的细胞运动模型，包括从分子/纤维尺度到全细胞尺度的过程。我们将通过开发基于微观细丝的模型来实现这一点，用于在前缘产生力，然后将这些模型整合到一个连续体描述中。我们将为子流程开发模块，这些子流程可以在不同的系统上单独测试，然后集成到完整的模型中。考虑到问题的复杂性，这种方法是必要的，但也是最佳的长期战略，因为它将允许为不同的系统使用不同的模块，并在新信息可用时促进合并。主要步骤的摘要如下。我们将在一个简单的几何结构中建立一个力生成的综合微观模型，并得到力-速度关系，然后将其应用于许多不同的实验构型。然后，我们将开发肌动蛋白动力学和力产生的连续描述，并在体腔细胞逆行流动的数据上进行测试，并将其适当修改应用于致病菌单核增生李斯特菌的肌动蛋白彗星尾。所有阶段都需要开发适当的计算工具。细胞运动在大多数生物生命周期的各个阶段都是必不可少的过程：多细胞生物的早期发育涉及个体和集体细胞运动，白细胞必须作为免疫反应的一部分向感染部位迁移，在癌症定向运动中涉及侵袭和转移。运动需要在细胞内产生力和与周围环境的机械相互作用，理解它们如何在空间和时间上被控制以产生细胞水平的运动是一个主要挑战。控制这些过程的分子网络的复杂性使得并非所有的相互作用都可以在计算模型的分子水平上进行；需要微观描述和连续描述的多尺度混合。目前还没有一种多尺度三维模型能够将微观水平的过程（纳米生物学）整合到细胞或组织水平的描述中。在全细胞模型的计算算法的发展方面已经取得了重大进展，提出的工作旨在开发一个新的微观模型的力在一个细胞中产生，并将微观模型集成到一个基于空间和时间变化的材料特性的多组分三维连续体描述。这项研究的一个重要成果将是一个围绕信号转导、力产生和运动的模块化描述构建的计算工具，它可以用来测试新的假设，并进行在实验室中难以进行的计算实验。

The overall objective of this project is to develop a multiscale model of cell motility that incorporates processes ranging from the molecular/filament scale to the whole-cell scale. We shall do this by developing microscopic filament-based models for force generation at the leading edge, and then integrating these into a continuum description. We will develop modules for the subprocesses that can be tested separately on different systems and then integrated into the complete model. This approach is necessary, given the complexity of the problem, but is also the best long-term strategy because it will allow for the use of different modules for different systems, and facilitate incorporation of new information as it becomes available. A summary of the major steps is as follows. We will formulate an integrated microscopic model of force generation in a simple geometry and obtain the force velocity relation, then apply this to a number of different experimental configurations. We will then develop the continuum description for actin dynamics and force generation and test it on data for retrograde flow in coelomocytes and apply it, suitably modified, to the actin comet tail in the pathogenic bacterium Listeria monocytogenes. All phases will require the development of appropriate computational tools. Cell movement is an essential process at various stages in the life cycle of most organisms: early development of multicellular organisms involves individual and collective cell movement, leukocytes must migrate toward sites of infection as part of the immune response, and in cancer directed movement is involved in invasion and metastasis. Movement entails force generation within cells and mechanical interactions with their surroundings, and understanding how they are controlled in space and time to produce cell-level movement is a major challenge. The complexity of the molecular network that controls these processes is such that not all interactions can be followed at the molecular level in a computational model; a multiscale hybrid of microscopic and continuum descriptions is needed. At present there is no multiscale three-dimensional model that integrates the microscopic-level processes (the nanobiology) into a cell- or tissue-level description. Significant progress on the development of computational algorithms for a whole-cell model has been made, and the proposed work is aimed at the development of a new microscopic model of force generation in a cell, and the integration of the microscopic model into a multicomponent 3D continuum description based on spatially- and temporally-varying material properties. A significant product of the research will be a computational tool built around modular descriptions for signal transduction, force generation, and movement that can be used to test new hypotheses and to do experiments computationally that are difficult to do in the laboratory.