Modeling Microtubule Dynamics in Mitosis

有丝分裂中的微管动力学建模

• 批准号: 7337319
• 负责人: David J. Odde
• 金额: $ 22.27万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7337319
• 关键词: Affect; Algorithms; Behavior; Biological; Biological Models; Biomedical Engineering; Cell Nucleus; Cell division; Cell physiology; Cells; Chemicals; Chemotaxis; Chromosomes; Collaborations; Complex; Computer Simulation; Computers; Coupled; Data; Development; Diffusion; Genome; Human; Individual; Intuition; Kinetochores; Life; Mechanics; Metaphase; Methods; Microscopy; Microtubules; Mitosis; Mitotic; Modeling; Molecular; Molecular Biology; Motion; Motor; Pattern; Physics; Plus End of the Microtubule; Process; Proteins; Range; Reaction; Recruitment Activity; Regulation; Research Personnel; Resolution; Role; Saccharomycetales; Salmon; Sister; Solutions; Speed; System; Technology; Testing; base; behavior influence; biological research; chromosome movement; computer code; design; digital; digital imaging; light microscopy; programs; rat Ran 2 protein; research study; simulation; stathmin; statistics; theories; tool

DESCRIPTION (provided by applicant): In cell division the actions of many molecules are integrated to mechanically segregate two complete genomes from each other via motions directly coupled to the dynamics of kinetochore microtubules. The extent of molecular-level-information relevant to cell division has increased substantially with the convergence of molecular biology and high-resolution digital light microscopy of living fluorescent protein- transfected cells. A major challenge now is to develop an understanding of cellular-level mechanisms from the vast amounts of quantitative molecular-level data. Importantly, the dynamic behavior of individual kinetochore microtubules remains to be determined. Fortunately, advances in high-speed computing make it increasingly practical to model complex processes such as microtubule dynamic instability and associated chromosome motions. The objective of this project will be to develop computer-based models to test hypotheses for the mechanisms controlling kinetochore microtubule dynamics in mitosis. Specifically, we will develop computational models to predict the separate and combined effects of motor-based polar ejection forces, stable chemical gradients, and mechanical tension in budding yeast mitosis. We will also develop reaction-diffusion models that generate the hypothesized chemical gradients, develop a theory for microtubule behavior in such gradients, and test the theory in LLCPK cells. In addition, we will develop an integrated mechanochemical model of microtubules embedded in the budding yeast kinetochore and test how mechanical force on the kinetochore can affect microtubule stability. In all cases models will be developed in ongoing collaborations with cell biologists, and the predictions compared directly to experimental observations. To facilitate these quantitative comparisons, we will implement models of high- resolution light microscopy to produce synthetic digital images of the fluorescent molecules in living cells and directly compare the model-predicted statistics to those obtained experimentally.

描述（由申请人提供）：在细胞分裂中，许多分子的作用被整合，通过与动粒微管动力学直接耦合的运动将两个完整的基因组彼此机械分离。与细胞分裂相关的分子水平信息的程度随着分子生物学和活荧光蛋白转染细胞的高分辨率数字光学显微镜的融合而大幅增加。现在的一个主要挑战是从大量的定量分子水平数据中了解细胞水平的机制。重要的是，个别动粒微管的动态行为仍有待确定。幸运的是，高速计算的进步使得对诸如微管动态不稳定性和相关的染色体运动等复杂过程进行建模变得越来越实用。本计画的目标是发展以电脑为基础的模型，以检验有丝分裂中控制动粒微管动力学的机制假说。具体来说，我们将开发计算模型来预测基于电机的极性喷射力，稳定的化学梯度和机械张力在芽殖酵母有丝分裂中的单独和组合效应。我们还将开发产生假设的化学梯度的反应扩散模型，开发这种梯度中微管行为的理论，并在LLCPK细胞中测试该理论。此外，我们将开发一个集成的机械化学模型的微管嵌入在芽殖酵母动粒和测试如何机械力的动粒可以影响微管的稳定性。在所有情况下，模型将在与细胞生物学家的持续合作中开发，并将预测直接与实验观察进行比较。为了促进这些定量比较，我们将实现高分辨率光学显微镜模型，以生成活细胞中荧光分子的合成数字图像，并直接将模型预测的统计数据与实验获得的统计数据进行比较。