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

合作研究：DMS/NIGMS 1：早期有丝分裂纺锤体组织的中尺度动力学理论

• 批准号: 2153399
• 负责人: Meredith Betterton
• 金额: $ 24.21万
• 依托单位: University of Colorado at Boulder
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2153399&HistoricalAwards=false
• 关键词: Collaborative; Research; DMS; NIGMS; Mesoscale

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.

为了使生命增殖，细胞必须在细胞分裂过程中忠实地将其遗传物质均等地分裂成两个新的子细胞。高度动态的双极有丝分裂纺锤体，由称为微管的蛋白质细丝构成，是完成这一基本任务所需的细胞机器。纺锤体组装过程中的错误与癌症等疾病有关。构建纺锤体的关键初始步骤包括分离形成纺锤体极的重复中心体。这涉及到结合并在微管上产生力的各种蛋白质。虽然机械相互作用是复杂的，但相关因素似乎足够小，可以用精确的生物物理术语分析它们的集体作用。该项目将结合联合收割机生物物理实验室实验，计算物理模型和统计参数化框架，以建立详细的了解如何纺锤体的形成是由不同的蛋白质组分的相互作用的影响。从方法论上讲，该研究旨在连贯地发展一种物理上可解释的早期纺锤体形成结构理论，该理论是自下而上建立的，在复杂性的各个阶段之间有着明确的联系。此外，数学、生物、物理的研究团队还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、生物的协作方法更好地理解生命科学中的重要过程。本项目的关键技术新奇将是构建中尺度动力学理论框架。该框架将通过统计总结处理纺锤体和相关蛋白质浓度，并通过为本项目设计的体外实验配置在复杂性增加的阶段进行参数化。理论模型将通过与计算模拟和新提出的体外实验相互作用来开发，这些实验涉及具有简化几何形状的虚拟星状体的微管束，通过光镊探测。该项目将利用现有的粗颗粒动力学理论来模拟交联剂介导的微管对对齐和非对齐的微管束之间的相互作用。相对于高度详细的动力学理论和基于单个交联剂和微管的详细计算的直接模拟，将寻求简化的统计描述。该研究将确定和利用关键的集体变量，以便在监管和环境因素以及由此产生的纺锤体动态之间建立更易于计算和透明的联系，这有助于为未来的实验产生假设。分级复杂性集成过程将使询问和纠正的物理假设，了解如何交联剂行为的微管对规模定量的微管bundle.This奖项反映了NSF的法定使命，并已被认为是值得的支持，通过评估使用基金会的智力价值和更广泛的影响审查标准。