Collaborative Research: DMS/NIGMS 1: Mesoscale Kinetic Theory of Early Mitotic Spindle Organization

为了让生命增殖，细胞必须在细胞分裂过程中忠实地将其遗传物质平均分裂为两个新的子细胞。高度动态的双极有丝分裂纺锤体，由被称为微管的蛋白质细丝组成，是完成这一基本任务所需的细胞机器。主轴组装过程中的错误被认为与癌症等疾病有关。构建纺锤体的一个关键的初始步骤是分离形成纺锤体极点的复制中心体。这涉及到多种蛋白质，它们结合在微管上并产生作用力。虽然机械相互作用很复杂，但相关因素的数量似乎很小，可以用精确的生物物理术语来分析它们的集体作用。该项目将结合生物物理实验室实验、计算物理模型和统计参数框架，以建立对纺锤体形成如何受到不同蛋白质成分相互作用影响的详细理解。在方法论上，这项研究的目的是一致地发展出一种早期纺锤体形成的物理上可解释的结构理论，该理论是自下而上建立的，复杂阶段之间有明确的联系。此外，来自数学、生物和物理的研究团队将为大学和当地高中的学生开展教育推广活动，强调如何利用数学、物理和生物学的协作方法来更好地了解生命科学中的重要过程。该项目的关键技术创新将是构建中尺度动力学理论框架。该框架将通过统计汇总来处理纺锤体和相关蛋白质的浓度，并通过为该项目设计的体外实验配置，在复杂性的增加阶段进行参数化。理论模型将通过与计算模拟和新提出的体外实验的相互作用来开发，该实验涉及具有简化几何形状的虚拟紫杉醇的微管束，并通过光钳进行探测。该项目将利用现有的粗粒动力学理论来模拟交联剂介导的微管对到排列和非排列的微管束之间的相互作用。将寻求与高度详细的动力学理论和基于单个交联剂和微管的详细核算的直接模拟相关的简化的统计描述。这项研究将确定和利用关键的集体变量，以便在调节和环境因素与由此产生的主轴动力学之间建立更易于计算和更透明的联系，这有助于为未来的实验生成假设。分级复杂性集成过程将允许询问和纠正有关理解微管对的交联剂行为如何定量扩展到微管束的物理假设。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

For life to proliferate, cells must faithfully divide their genetic material equally into two new daughter cells during cell division. The highly dynamic bipolar mitotic spindle, built from protein filaments called microtubules, is the cellular machine needed to accomplish this essential task. Errors in the spindle assembly process have been linked to diseases such as cancer. A critical initial step in building the spindle involves the separation of duplicated centrosomes that form the spindle poles. This involves a variety of proteins that bind and generate a force on the microtubules. While the mechanical interplay is complex, the relevant factors appear small enough in number that their collective action can be analyzed in precise biophysical terms. This project will combine biophysical laboratory experiments, computational physical models, and statistical parameterization frameworks in order to build detailed understanding of how spindle formation is affected by the interaction of the diverse protein components. Methodologically, the research aims to coherently evolve a physically interpretable structural theory of early spindle formation that is built bottom-up with clear linkages between stages of complexity. Additionally, the research team from mathematical sciences, biology, and physics will develop educational outreach activities for students at the universities and local high schools, emphasizing how collaborative methodologies from mathematics, physics, and biology can be deployed to better understand vital processes in the life sciences.The key technical novelty of this project will be the construction of a mesoscale kinetic theory framework. The framework will treat the spindle and associated protein concentrations through statistical summaries and be parameterized in increasing stages of complexity through in vitro experimental configurations designed for this project. The theoretical model will be developed through interaction with computational simulations and newly proposed in vitro experiments involving microtubule bundles with virtual asters in simplified geometries, probed by optical tweezers. The project will exploit the coarse-grains existing kinetic theory to model crosslinker-mediated interactions between pairs of microtubules to aligned and non-aligned bundles of microtubules. A reduced statistical description will be sought relative to highly detailed kinetic theories and direct simulation based on a detailed accounting of individual crosslinkers and microtubules. The research will identify and exploit key collective variables for a more computationally tractable and transparent connection between regulatory and environmental factors and the resulting spindle dynamics, which can aid in generating hypotheses for future experiments. The graded complexity integration process will enable interrogation of and corrections to physical assumptions regarding understanding how crosslinker behavior for microtubule pairs scales up quantitatively to microtubule bundles.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.