COMPUTER SIMULATION OF MECHANOCHEMICAL COUPLING IN CELLS

描述定向细胞爬行对于胚胎发育中的神经分布、角质形成细胞在伤口部位的迁移、中性粒细胞追逐和清除异物以及癌细胞侵入健康组织是必不可少的。这项研究是一个细胞内信号与细胞骨架重组和主动作用力产生相结合的综合计算模型。长期目标是更好地理解外部趋化物质梯度是如何转化为内部信号的，从而协调外部趋化物质梯度如何转化为协调肌动蛋白细胞骨架极化重排和激活的内部信号。研究金期间的具体目标是将申请者以前开发的计算技术应用于并增强特定的生物系统。计算模型的输入将是分子水平上已知化学和机械事件的微米平均解释。模型的输出将是受刺激细胞的极化、变形和由此产生的运动，它将与现有的关于细胞形状变化和趋化性的实验数据进行比较。将使用研究得很好的模式生物盘基网柄菌来验证计算模型。在这一点上，该模型将被修改为研究哺乳动物细胞，如人类中性粒细胞和角质形成细胞。然后可以确定现有的向细胞骨架发出信号的理论是否足以产生这些爬行细胞的实验观察行为。该模型还可用于确定足以产生与在活细胞中观察到的运动相似的运动的最小信号机制集。

DESCRIPTION Directed cell crawling is essential for nerve distribution in embryonic development, the migration of keratinocytes across a wound site, the pursuit and elimination of foreign particles by neutrophils, and the invasion of cancerous cells into healthy tissue. The proposed research is an integrative computational model of intracellular signaling coupled to cytoskeletal reorganization and active force generation in crawling cells The long-term goal is to develop a better understanding of how an external chemoattractant gradient is transduced into an internal signal that coordinates the understanding of how an external chemoattractant gradient is transduced into an internal signal that coordinates the polarized rearrangement and activation of the actin cytoskeleton. The specific aim during the course of the fellowship is to apply and enhance computational technique previously developed by the applicant to specific biological systems. Inputs into the computational model will be micron- scale-averaged interpretations of known chemical and mechanical events at the molecular level. The model output will be the polarization, deformation and resulting locomotion of the stimulated cell, which will be compared to available experimental data on cell shape change and chemotaxis. The well-studied model organism Dictyostelium discoideum will be used to validate the computational model. At this point the model will be modified to study mammalian cells, such as human neutrophils and keratinocytes. It may then be determined whether existing theories of signaling to the cytoskeleton are sufficient to produce the experimentally observed behavior of these crawling cells. The model may also be used to identify a minimal set of signaling mechanisms that suffice to produce motion similar to that observed in living cells.