Mathematical Modeling and Computational Analysis of Cell 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，并且在癌症转移中具有有害作用。运动是一个复杂的过程，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”或“滑动”，包括手指状突起和/或宽而平的突起的延伸，其突起是由前缘的肌动蛋白聚合驱动的。变形虫模式较少依赖于强附着力，细胞更圆，并利用形状变化来移动——实际上是“挤过人群”或“游泳”。当黏附分子被敲除时，免疫系统的细胞使用这种模式在组织中运动。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相应地调整它们的运动模式。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，以确定在给定环境中最有效的策略。这项研究的长期目标是了解细胞如何感知环境的机械特性，并将这些信息转化为细胞内的生化和机械变化，从而决定它们的运动模式。最近的实验工作发现，许多细胞类型在细胞壁附近使用强大的细胞内物质流，当这种物质流被破坏时，细胞运动就会中断。然而，对这种流动如何转化为细胞运动的理解还很少，我们的第一个目标是继续开发和分析一个数学模型，该模型有助于在硅实验中了解所涉及的过程如何相互作用以产生运动。另一个目标是了解细胞骨架的变化，以产生运动所需的气泡，这是“水泡样”的膜突起，以及如何在复杂的环境中选择气泡和其他模式。特别是，膜张力的作用和细胞约束的性质决定了膜上的气泡如何和在哪里开始，以及是否使用气泡或突起，尚不清楚。第三个目标涉及在各种形式的禁闭下细胞的运动。众所周知，施加的机械应力可以诱导其他静止细胞的运动，但机械刺激如何诱导运动尚不清楚。PI将开发的详细模型将提供实验可测试的预测，可用于指导新的实验，从而提高我们对细胞运动的理解。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Cell locomotion plays an essential role during embryonic development, angiogenesis, tissue regeneration, the immune response, and wound healing in multicellular organisms, and has a deleterious effect in cancer metastasis. Movement is a complex process that involves the spatial and temporal control and integration of a number of sub-processes, including the transduction of chemical or mechanical signals from the environment, intra-cellular 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' or `gliding', involves the extension of finger-like protrusions and/or broad, flat protrusions, whose protrusion is driven by actin polymerization at the leading edge. The amoeboid mode is less reliant on strong adhesion, and cells are more rounded and employ shape changes to move -- in effect 'jostling through the crowd' or `swimming'. Cells of the immune system use this mode for movement through tissues when adhesion molecules have been knocked out. 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 their mode of movement accordingly. Thus pure crawling and pure swimming are the extremes on a continuum of locomotion strategies, but many cells can sense their environment to determine the most efficient strategy in a given environment.The long-term objective in this research is to understand how cells sense the mechanical properties of their environment and transduce the information into intracellular biochemical and mechanical changes that determine their pattern of movement. Recent experimental work has discovered that numerous cell types use strong intracellular material flows near the cell wall, which, when disrupted, disruptscell movement. However, there is as yet little understanding of how this flow translates into cell movement, and our first objective is to continue development and analysis of a mathematical model that facilitates in silico experiments to understand how the processes involved interact to produce motion. Another objective is to understand the cytoskeletal changes needed to produce motion using blebs, which are 'blister-like' protrusions of the membrane, and how the choice between blebs and other modes is arbitrated in complex environments. In particular, the role of membrane tension and the nature of cell confinement in determining how and where on the membrane blebs are initiated, and whether blebs or protrusions are used, are not understood. A third objective concerns movement of cells under various forms of confinement. It is known that imposed mechanical stress can induce movement in otherwise quiescent cells, but how mechanical stimuli induce motion is not understood. A detailed model such as the PI shall develop will provide experimentally-testable predictions that can be used to guide new experiments that advance our understanding of cell movement.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.