Mechanochemical Regulation of the Motile Cell Shape

细胞运动是一种重要的生理现象，在生物学和医学领域都受到广泛关注。它是基于一个显着的自组织机械化学机器，包括亚细胞模块，如（i）肌动蛋白为基础的突起，（ii）肌球蛋白动力收缩，（iii）分级粘附，（iv）膜阻力。虽然这些模块的分子库存变得可用，但缺乏对运动细胞在系统生物学水平上的理解。这种理解必须首先针对简单形状的细胞，例如鱼上皮角膜细胞来实现。本研究的目的是使用数学分析，计算机模拟和模型驱动的实验的一种新的组合，将亚细胞运动模块整合到一个多尺度的运动角膜细胞的计算模型。这些工具将被用来发现细胞中是否存在影响分子扩散运输的显著胞质流，分子马达和膜在静止和运动细胞的稳定性中的作用，以及整合决定运动细胞形状的亚细胞运动模块的精确方式。胚胎发生和癌症转移。细胞通过以下方式移动：（i）在前部延伸伸展的附属物，（ii）在内部发展收缩，以及（iii）在前部与表面形成牢固的粘附，在后部形成弱粘附。虽然这三个步骤的分子机制越来越清楚，但缺乏对运动细胞作为一个系统的理解。该项目将提供对细胞运动动力学的系统级理解，并导致爬行细胞的预测模型。该模型将有助于设计实验，阐明细胞运动行为在重要的生理和医学系统。通过参与本研究项目培训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.