Computational Models of Cell Division

描述(由申请人提供)：在细胞分裂的最后阶段，即胞质分裂，细胞在形态上经历了戏剧性的变化，因为它们重新排列自己，以产生两个相同的子细胞。要详细了解这些过程是如何调控的，需要了解不同的细胞骨架蛋白是如何在空间和时间上受到调控的，以及由此产生的异质性如何影响细胞的机械性能。这些过程的复杂性使得如果没有一个允许对想法和概念模型进行计算机测试的建模框架，就几乎不可能理解。为了阐明细胞调节胞质分裂的机制，我们需要了解生化信号信号的调节如何影响细胞形态的变化。我们将开发一个合适的计算框架来研究在胞质分裂过程中细胞骨架蛋白的生化调节导致所需细胞变形的方式。我们的模拟将用于将计算模拟与不同蛋白质在胞质分裂期间的时间和空间变化以及相关的细胞形状变化的定量测量相结合。具体地说，我们建议：1.开发一个计算框架来模拟整个细胞，细胞在有丝分裂过程中的形状变化；2.使用相互作用的细丝的离散网络表示，开发一个基于代理的肌动蛋白细胞骨架模型，并使用该模型来研究细胞分裂过程中细胞的形态变化。 公共卫生相关性：长期以来，成功的细胞分裂一直被认为对人类健康至关重要。许多癌症相关基因导致有丝分裂和/或细胞分裂失败。在这项研究中，我们结合计算和实验工具来研究细胞调节其机械性能的方式，以确保每个母细胞成功地分裂成两个大小相等的子细胞。

DESCRIPTION (provided by applicant): During the last stage of cell division, cytokinesis, cells undergo a dramatic change in morphology as they rearrange themselves so as to produce two identical daughter cells. A detailed understanding of how these processes are regulated requires a fundamental knowledge of how different cytoskeletal proteins are spatially and temporally regulated, and how the resultant heterogeneity affects the mechanical properties of the cell. The complexity of these processes makes it nearly impossible to understand without a modeling framework that allows in silico testing of ideas and conceptual models. To elucidate the mechanisms by which cells regulate cytokinesis we need to appreciate how regulation of biochemical signaling cues effect changes in cell morphology. We will develop a suitable computational framework for studying the way in which biochemical regulation of cytoskeletal proteins results in desired cellular deformations during cytokinesis. Our simulations will be used to integrate computational modeling with quantitative measurements of the temporal and spatial changes of different proteins and the associated changes in cell shape during cytokinesis. Specifically, we propose: 1. to develop a computational framework for simulating whole cell, cell shape changes during mitosis; 2. to develop an agent-based model of the actin cytoskeleton using a discrete-network representation of interacting filaments, and to use this model to investigate cell morphological changes during cytokinesis. PUBLIC HEALTH RELEVANCE: Successful cell division has long been appreciated as critical to human health. Many cancer- associated genes lead to mitotic and/or cytokinetic failure. In this research we combine computational and experimental tools to study the way that cells regulate their mechanical properties to ensure that each mother cells successfully divides into two equally-sized daughter cells.