EAGER: Biophysical Theory of Mitotic Spindle Length Instability and Self Assembly

该奖项是根据EAGER提案设立的，它支持有丝分裂纺锤体长度不稳定性和自组装的生物物理理论的理论研究和教育。真核细胞有丝分裂纺锤体是细胞骨架的重要组成部分。它是一种自组装的三维结构，主要由由特定蛋白质制成的管状结构组成，它在细胞分裂过程中充当分离染色体的分子机器。这项研究计划的最终目标是提供一个基本问题的答案：“有丝分裂纺锤体，一个具有恒定分子周转的非平衡结构，如何能够i)自组装，ii)保持固定长度。”PI计划在从纳米到微米的多个尺度上对纺锤体长度动力学和自组装进行建模，将统计物理学、分子生物物理学、结构生物学、分子生物学和细胞生物学的思想结合在一起。这项工作有一个涉及大规模建模框架的非常重要的计算组件。PI打算通过开源许可证免费提供开发的软件。细胞自组织并动态生成复杂的三维结构。灯丝成核，聚合和相互作用驱动的重排在空间和时间上受到调节，以构建各种各样的组装。在自组织细胞骨架结构的研究中，一个重要的一般性问题是如何整合分子水平的知识来预测组装和组织的高阶方面。一个典型的自组装细胞骨架结构是有丝分裂纺锤体，这是一个基于微管的机器，在真核细胞分裂过程中分离染色体。该项目将创建一个裂变酵母有丝分裂纺锤体的物理理论，概述纺锤体长度的稳定性/波动和双极纺锤体组装，以解决具有恒定分子周转的非平衡结构如何自我组装并保持固定长度的基本问题。这个项目有三个组成部分。PI将首先开发必要的模型成分，包括多种电机/交联，新型电机力-速度关系，电机/交联的两阶段绑定/解绑定以及动态微管。然后，PI将通过整合从纳米到微米尺度的模型，确定有丝分裂纺锤体长度波动和纺锤体长度稳定的机制。这个部分将导致主轴长度动态稳定的定量物理理论的发展。随后，PI将确定在裂变酵母有丝分裂纺锤体的最小模型中双极束组装所需的成分。这项工作将涉及计算屏幕，以找到与稳定的纺锤状微管束自组装相关的模型/参数空间区域，并与层析模型进行比较。这项工作有一个涉及大规模建模框架的非常重要的计算组件。PI打算通过开源许可证免费提供开发的软件。

NONTECHNICAL SUMMARYThis award is made on an EAGER proposal, and it supports theoretical research and education on the biophysical theory of mitotic spindle length instability and self-assembly. The mitotic spindle is an important part of the cytoskeleton in eukaryotic cells. It is a self-assembled three-dimensional structure, primarily composed of tubes made from specific proteins, and it functions as a molecular machine that separates chromosomes during cell division. The ultimate goal of this research program is to provide an answer to the fundamental question: "How can the mitotic spindle, a non-equilibrium structure with constant molecular turnover i) self-assemble, and ii) maintain a fixed length." The PI intends to model the spindle length dynamics and self-assembly at multiple scales, ranging from nanometer to micron, bringing together ideas from statistical physics, molecular biophysics, structural, molecular, and cellular biology. The effort has a very substantial computational component involving a large-scale modeling framework. The PI intends to make the developed software freely available through an open-source license.TECHNICAL SUMMARYCells self-organize and dynamically generate complex three-dimensional structures. Filament nucleation, polymerization, and interaction-driven rearrangement are regulated in space and time to construct a wide variety of assemblies. An important general question in the study of self-organized cytoskeletal structures is how to integrate molecular-level knowledge to predict higher-order aspects of assembly and organization. A prototypical self-assembled cytoskeletal structure is the mitotic spindle, a microtubule-based machine that segregates chromosomes during eukaryotic cell division. This project will create a physical theory of the fission yeast mitotic spindle that recapitulates spindle length stability/fluctuations and bipolar spindle assembly to address the fundamental question of how a non-equilibrium structure with constant molecular turnover can self-assemble and maintain a fixed length. This project has three components. The PI will first develop essential model ingredients including multiple species of motors/crosslinks, novel motor force-velocity relations, two-stage binding/unbinding of motors/crosslinks, and dynamic microtubules. Then the PI will determine the mechanisms underlying mitotic spindle length fluctuations and stabilization of spindle length through the integration of models that span from nanometer to micron scales. This component will lead to the development of a quantitative physical theory of dynamic stabilization of spindle length. Subsequently, the PI will determine the ingredients necessary for bipolar bundle assembly in a minimal model of the fission yeast mitotic spindle. This work will involve computational screens to find regions of model/parameter space associated with self-assembly of a stable spindle-like microtubule bundle and comparison to tomographic models. The effort has a very substantial computational component involving a large-scale modeling framework. The PI intends to make the developed software freely available through an open-source license.