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、角质形成细胞穿过伤口部位的迁移、中性粒细胞对外来颗粒的追踪和清除以及癌细胞侵入健康组织至关重要。拟议的研究是一个整合的计算模型的细胞内信号耦合到细胞骨架重组和主动力的产生在爬行细胞的长期-术语目标是更好地理解外部化学引诱物梯度如何被转导成内部信号，该内部信号协调理解外部化学引诱物梯度如何被转导成内部信号，该内部信号协调极化重排和激活肌动蛋白细胞骨架。研究金课程的具体目标是将申请人以前开发的计算技术应用和加强到特定的生物系统。输入到计算模型中的将是在分子水平上对已知化学和机械事件的微米尺度平均解释。模型输出将是受刺激细胞的极化、变形和由此产生的运动，这将与细胞形状变化和趋化性的可用实验数据进行比较。研究的模式生物盘基网柄藻将被用来验证计算模型。在这一点上，该模型将被修改，以研究哺乳动物细胞，如人类中性粒细胞和角质形成细胞。然后可以确定现有的信号传导到细胞骨架的理论是否足以产生实验观察到的这些爬行细胞的行为。该模型还可以用于识别足以产生类似于在活细胞中观察到的运动的信号机制的最小集合。

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.