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

非技术总结该奖项是由一项热切的提议颁发的，它支持关于有丝分裂纺锤体长度不稳定和自组装的生物物理理论的理论研究和教育。有丝分裂纺锤体是真核细胞中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组成，它的功能是在细胞分裂期间分离染色体的分子机器。这一研究计划的最终目的是给出一个基本问题的答案：有丝分裂纺锤体是一种分子周转不断的非平衡结构，如何才能自我组装，以及ii)保持固定的长度。PI打算在从纳米到微米的多个尺度上模拟主轴长度动态和自组装，集合了统计物理、分子生物物理、结构、分子和细胞生物学的想法。这项工作有一个非常重要的计算部分，涉及一个大规模的建模框架。PI的目的是通过开放源码许可证免费提供开发的软件。TECHNICAL SUMMARYCells自组织并动态生成复杂的三维结构。细丝成核、聚合和相互作用驱动的重排在空间和时间上受到调控，以构建各种不同的组装。在自组织细胞骨架结构研究中的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，这是一种基于微管的机器，在真核细胞分裂期间分离染色体。这个项目将创建一个分裂酵母有丝分裂纺锤体的物理理论，它概括了纺锤体长度的稳定性/波动和两极纺锤体组装，以解决分子周转恒定的非平衡结构如何自组装并保持固定长度的根本问题。这个项目有三个组成部分。PI将首先开发基本的模型成分，包括多种马达/交联物、新颖的马动力-速度关系、马达/交联物的两阶段结合/解绑以及动态微管。然后，PI将通过整合从纳米到微米尺度的模型来确定有丝分裂纺锤体长度波动和纺锤体长度稳定的潜在机制。这一组成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将确定在分裂酵母有丝分裂纺锤体的最小模型中组装双极束所需的成分。这项工作将涉及计算机筛选，以寻找与稳定的纺锤形微管束的自组装相关的模型/参数空间区域，并与断层模型进行比较。这项工作有一个非常重要的计算部分，涉及一个大规模的建模框架。PI打算通过开放源码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.