Mechanochemical Regulation of the Motile Cell Shape

细胞运动是一种重要的生理现象，在生物学和医学上备受关注。它基于一种非凡的自组织机械力化学机器，由亚细胞模块组成，例如(I)基于肌动蛋白的突起，(Ii)肌球蛋白动力收缩，(Iii)分级粘连，和(Iv)膜阻力。虽然这些模块的分子清单正在变得可用，但在系统生物学水平上对活动细胞的了解还很欠缺。首先必须对简单形状的细胞，如鱼类上皮细胞，实现这一理解。这项研究的目的是利用数学分析、计算机模拟和模型驱动实验的新组合，将亚细胞运动模块集成到运动性角质细胞的多尺度计算模型中。这些工具将被用来找出细胞内是否有显著的细胞质流动影响分子的扩散运输，分子马达和膜在静止和运动细胞的稳定性中扮演的角色是什么，以及整合决定运动细胞形状的亚细胞运动模块的准确方式是什么。细胞运动一直是人们对细胞运动的巨大兴趣--伤口愈合、胚胎发育和癌症转移背后的普遍现象。细胞通过以下方式移动：(I)在前部伸出突出的附属物，(Ii)在内部发生收缩，(Iii)在前部与表面形成牢固的粘连，在后部形成较弱的粘附力。虽然这三个步骤的分子机制正在变得清晰，但对运动细胞作为一个系统的理解还很欠缺。该项目将提供对细胞运动动力学的系统级理解，并产生爬行细胞的预测模型。该模型将有助于设计实验，阐明细胞在重要的生理和医学系统中的运动行为。通过参与这一研究项目培养的学生将成为新一代跨学科研究力量的一部分。

Cell motility is an important physiological phenomenon attracting much attention in biology and medicine. It is based on a remarkable self-organized mechanochemical machine that consists of subcellular modules, such as (i) actin based protrusion, (ii) myosin powered contraction, (iii) graded adhesion, and (iv) membrane resistance. While molecular inventories of these modules are becoming available, understanding of the motile cell at the systems biology level is lacking. This understanding has to be achieved first for the simple shaped cells, such as fish epithelial keratocytes. The objective of this research is to use a novel combination of mathematical analysis, computer simulations and model-driven experiments to integrate the subcellular motility modules into a multi-scale computational model of the motile keratocyte cell. These tools will be used to find out whether there is a significant cytoplasmic flow in the cell affecting diffusive transport of molecules, what is the role of molecular motors and membrane in stability of stationary and motile cells, and what is the precise way of integrating subcellular motility modules determining motile cell shape.There has been enormous interest in cell motility--ubiquitous phenomenon underlying wound healing, embryogenesis and cancer metastasis. Cells move by (i) extending protrusive appendages at the front, (ii) developing contractions inside, and (iii) forming firm adhesion to the surface at the front and weak at the rear. While molecular mechanisms of these three steps are becoming clear, understanding of the motile cell as a system is lacking. This project will provide systems-level understanding of the cell motility dynamics and result in predictive model of the crawling cell. The model will help to design experiments that will elucidate cell motile behavior in important physiological and medical systems. Students trained through involvement in this research project will become part of a new generation of interdisciplinary research force.