Computation & mechanical modeling of chromosome dynamics

计算

• 批准号: 6898333
• 负责人: PETER Karl SORGER
• 金额: $ 35.99万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-15 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6898333
• 关键词: Saccharomyces cerevisiae; biomechanics; centromere; charge coupled device camera; chromosome movement; computer program /software; computer simulation; computer system design /evaluation; cytogenetics; gene mutation; green fluorescent proteins; mathematical model; microtubules; mitotic spindle apparatus; model design /development; yeast two hybrid system

DESCRIPTION (provided by applicant): The goals of this study are to determine how S. cerevisiae kinetochores bind to microtubules and how them forces required for chromosome movement are generated. This will be accomplished by linking systematic experiments to quantitative analysis. A mechanical model of the spindle will be developed combining explicit numerical representations of cellular mechanics with molecular detail. Chromosome segregation is the process by which replicated DNA molecules are pulled into daughter cells by attaching to and moving along the microtubules of the mitotic spindle. Chromosome-microtubule attachment is mediated by kinetochores, multi-component protein complexes that form on centromeric DNA. S. cerevisiae is an attractive organism in which to study kinetochores because it contains the simplest of all known centromeres. In addition, the powerful molecular genetics of budding yeast make it straightforward to engineer specific lesions into spindle and kinetochores proteins and to monitor the phenotypic consequences. The conservation of kinetochore proteins from yeast to man suggests that principles learned from the study of simple yeast kinetochores will be applicable to complex kinetochores in higher cells. The following specific aims will be addressed: Aim 1: Systematic analysis of chromosome movement will be performed at different phases of the cell cycle and in cells in which spindle geometry has been perturbed genetically. Aim 2: Machine vision algorithms incorporating biological prior knowledge will be developed for superresolution tracking of chromosome movement in living cells Aim 3: Numerical models of spindle mechanics will be formulated in which various force-generating mechanisms can be explored through simulation and subsequent experimentation. Aim 4: Mutations will be introduced into kinetochores genes implicated in force generation and phenotypes analyzed with reference to computational models of spindle function.

描述（由申请人提供）：这项研究的目标是确定酿酒酵母动物链球菌如何与微管结合以及如何产生染色体运动所需的力。这将通过将系统实验与定量分析联系起来来实现。将开发主轴的机械模型，将细胞力学的显式数值表示与分子细节相结合。 染色体隔离是通过连接到有丝分裂纺锤体的微管并移动到子细胞中的复制DNA分子的过程。染色体 - 微管附着是由在丝粒DNA上形成的多组分蛋白复合物动力学介导的。 酿酒酵母是一种吸引人的生物体，可以在其中研究动力学，因为它包含所有已知的丝粒中最简单的生物。此外，发芽的酵母的强大分子遗传学使其直接地将特定的病变设计到纺锤体和动力学蛋白中，并监测表型后果。 从酵母到人的动核蛋白的保护表明，从简单酵母动物学的研究中学到的原理将适用于较高细胞中的复杂的动物学。 将解决以下具体目标： AIM 1：染色体运动的系统分析将在细胞周期的不同阶段和纺锤几何形状受到遗传扰动的细胞中进行。 AIM 2：将开发包含生物学先验知识的机器视觉算法，以用于追踪活细胞中染色体运动 AIM 3：将制定主轴力学的数值模型，其中可以通过模拟和随后的实验探索各种力的生成机制。 AIM 4：突变将引入涉及力产生的动力学基因，并参考纺锤函数的计算模型分析的表型。