Mathematical Modeling and Computational Analysis of Cell Movement

在多细胞生物体中，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等过程中起着至关重要的作用，并在肿瘤转移中起着有害的作用。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，细胞内的生化反应，以及将细胞内和细胞外的信号转化为机械反应。虽然许多单细胞生物利用鞭毛或纤毛游泳，但真核细胞使用的两种基本运动方式缺乏这种结构--间充质和变形体。前者可称为“爬行”或“滑行”，涉及指状突起和/或宽阔、平坦的突起，其突起是由前沿的肌动蛋白聚合驱动的。阿米巴模式对强黏附的依赖程度较低，细胞更圆，会利用形状变化来移动--实际上是“在人群中推挤”或“游泳”。当黏附分子被清除时，免疫系统的细胞使用这种模式在组织中移动。然而，最近的实验表明，许多类型的细胞在运动中表现出巨大的可塑性，因为它们可以感知环境的机械特性，并相应地调整自己的运动方式。因此，纯粹的爬行和纯粹的游泳是运动策略连续体中的极端，但许多细胞可以感知环境，以确定在给定环境中最有效的策略。本研究的长期目标是了解细胞如何感知环境的机械特性，并将信息转化为决定其运动模式的细胞内生化和机械变化。最近的实验工作发现，许多类型的细胞使用靠近细胞壁的强大的细胞内物质流，当细胞被破坏时，这种物质流破坏细胞的运动。然而，到目前为止，人们对这种流动如何转化为细胞运动的了解还很少，我们的第一个目标是继续开发和分析一个数学模型，该模型有助于在计算机实验中理解所涉及的过程如何相互作用来产生运动。另一个目标是了解使用气泡产生运动所需的细胞骨架变化，气泡是膜的“水泡状”突起，以及如何在复杂的环境中仲裁气泡和其他模式之间的选择。特别是，膜张力的作用和细胞限制的性质决定了膜上气泡的启动方式和位置，以及是使用气泡还是使用突起，目前还不清楚。第三个目标涉及在各种形式的监禁下的细胞移动。众所周知，施加的机械应力可以在原本静止的细胞中诱导运动，但机械刺激如何诱导运动尚不清楚。像PI将开发的详细模型将提供可实验测试的预测，这些预测可用于指导新的实验，以促进我们对细胞运动的理解。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.