Mathematical modeling and Computational Analysis of Cell Tissue Movement

在多细胞生物中，细胞运动在胚胎发育、血管生成、组织再生、免疫反应和伤口愈合过程中起着至关重要的作用。在这个项目中要解决的主要问题是：(i)由形状变化引起的运动，（ii）细胞内力学的建模，以及（iii）在细胞运动的综合计算模型中整合信号，肌动蛋白动力学和力学。到目前为止，数学模型主要集中在间质模式，但研究人员首先解决了连续体的另一端。总的目标是产生一个统一的描述运动在一个三维细胞外基质，整合信号和力学。形状变化的运动尚未在提出的背景下进行研究，但它最近被证明在许多细胞类型的运动中很重要，并且理解影响这种运动速度和效率的因素是一个具有挑战性的问题。该项目开发了数学模型，可用于研究和量化影响运动效率的各种因素的重要性，例如周围介质的特性。第三部分将继续首席研究员之前在信号方面的工作，并将控制网络模型与组成第一个主题的机械组件集成在一起。这将导致第一个结合信号和力学的模型，并将产生一个对更广泛的社区非常有用的计算工具。细胞运动是一个非常复杂的过程，涉及许多子过程的时空控制和整合，包括来自环境的化学或机械信号的转导，细胞内生化反应，以及细胞内和细胞外信号转化为机械反应。虽然许多单细胞生物使用鞭毛或纤毛来游泳，但真核细胞使用两种基本的运动模式，即间充质细胞和变形虫细胞，它们缺乏这种结构。前者可以被描述为“爬行”。在成纤维细胞或？滑翔？在角化细胞中，包括指状伪足和/或宽扁平板足的延伸，其突出是由前缘的肌动蛋白聚合驱动的。在变形虫模式下，细胞不依赖于强附着力，细胞更圆，并通过形状变化来移动——实际上是“挤过人群”或“游泳”。然而，最近的实验表明，许多细胞类型在运动中表现出巨大的可塑性，因为它们感知环境的机械特性并调整模式之间的平衡。因此，纯粹的爬行和纯粹的游泳是连续运动策略的极端，但许多细胞可以感知它们的环境，并在给定的环境中使用最有效的策略。本项目采用创新的数学方法，结合新颖的模型和实验数据，更好地理解细胞运动的动力学。此外，研究团队包括博士后研究人员和研究生，该项目提供了一个在跨学科领域工作的机会。

Cell locomotion plays an essential role during embryonic development, angiogenesis, tissue regeneration, the immune response, and wound healing in multicellular organisms. The major problems to be addressed in this project are (i) movement by shape changes, (ii) modeling of the intracellular mechanics, and (iii) integration of signaling, actin dynamics and mechanics in an integrated computational model of cell movement. Heretofore mathematical modeling has primarily focused on the mesenchymal mode, but the investigators first address the other end of the continuum. The overall objective is to produce a unified description for locomotion in a three-dimensional extracellular matrix that integrates signaling and mechanics. Movement by shape changes has not been studied in the context proposed, but it has recently been shown to be important in the movement of a number of cell types, and understanding the factors that affect the speed and efficiency of such movement is a challenging problem. This project develops mathematical models that can be used to study and quantify the importance of various factors, such as properties of the surrounding medium, that affect the efficiency of movement. The third component continues previous work by the principal investigator on signaling and will integrate a model of the control networks with the mechanical components that comprise the first topics. This will lead to the first model that incorporates both signaling and mechanics, and will result in a computational tool that should be very useful to the broader community.Cell movement is a very complex process that involves the spatial and temporal control and integration of a number of subprocesses, including the transduction of chemical or mechanical signals from the environment, intracellular biochemical responses, and translation of the intra- and extracellular signals into a mechanical response. While many single-celled organisms use flagella or cilia to swim, there are two basic modes of movement used by eukaryotic cells that lack such structures--mesenchymal and amoeboid. The former, which can be characterized as ?crawling? in fibroblasts or ?gliding? in keratocytes, involves the extension of finger-like pseudopodia and/or broad flat lamellipodia, whose protrusion is driven by actin polymerization at the leading edge. In the amoeboid mode, which does not rely on strong adhesion, cells are more rounded and employ shape changes to move--in effect 'jostling through the crowd' or 'swimming'. However, recent experiments have shown that numerous cell types display enormous plasticity in locomotion, in that they sense the mechanical properties of their environment and adjust the balance between the modes. Thus pure crawling and pure swimming are the extremes on a continuum of locomotion strategies, but many cells can sense their environment and use the most efficient strategy in a given context. This project uses innovative mathematical approaches to better understand the dynamics of cell locomotion, combining novel models with experimental data. Additionally, the research team includes postdoctoral researchers and graduate students, with the project providing an opportunity to work in an inherently interdisciplinary field.