Understanding mitotic spindle positioning by integrated modeling and experiment

有丝分裂纺锤体在细胞分裂过程中形成，并将染色体分离成子细胞。它是正常真核细胞分裂所必需的。在大多数细胞中，分裂面位置和方向是由纺锤体位置和方向控制的。然而，主轴定位的力机制尚不清楚。人们提出了两种可供选择的模型。一种是与细胞皮层的微管相互作用，另一种是与细胞质的微管相互作用。目标是通过对秀丽隐杆线虫早期胚胎进行建模、模拟和实验，找出哪一种模型（如果不是两者都正确的话）是正确的。项目团队具备生物物理理论、实验、数学建模和仿真方面的技能。两种模型的本质区别在于微管是主动还是被动地与细胞质相互作用，但考虑到系统的复杂性，仅凭实验很难区分。我们将使用建模和模拟来预测与每个模型及其组合相关的细胞质流动，并将这些与实际流动的实验测量结果进行比较。详细的流体动力学相互作用在以前的纺锤体动力学建模中没有考虑到，并且需要新的方法来有效和准确地捕获纺锤体微管相互作用、细胞质液和细胞周围。我们将把预测的动力学与同时捕获纺锤体结构和动力学以及细胞质运动的新实验测量进行比较。将比较在物理、分子和遗传扰动下预测和观察到的反应。智力优势：提出的工作将带来一个新的方法来模拟有丝分裂纺锤体动力学和定位。综合实验和理论方法将使新的见解定位和不对称细胞分裂的机制。该项目将有助于更广泛地了解有丝分裂纺锤体和细胞分裂，这是细胞生物学中一个长期存在的基本问题。这项工作将扩展在细胞生物学、生物物理学、实验技术、统计物理学、应用数学、流体动力学、偏微分方程和数值分析方面的技术知识。

The mitotic spindle forms during cell division and separates chromosomes into the daughter cells. It is required for normal eukaryotic cell division. In most cells, the division plane position and orientation is controlled by spindle position and orientation. However, the force mechanisms underlying spindle positioning are ill-understood. Two alternative models have been proposed. One invokes microtubule interactions with the cell cortex, and the other with the cell cytoplasm. The goal is to discover which model (if not both) is correct by using modeling, simulation, and experiments in C. elegans early embryos. The project team has skills in biophysical theory, experiment, mathematical modeling, and simulation. An essential difference between the two models is whether microtubules interact actively or passively with the cytoplasm, but given the system's complexity it is difficult to discriminate with experiment alone. We will use modeling and simulation to predict cytoplasmic flows associated with each model, and their combinations, and compare these to experimental measurements of actual flows. Detailed hydrodynamic interactions have not been previously accounted for in modeling spindle dynamics, and requires novel methods for efficiently and accurately capturing spindle microtubules interacting with each other, the cytoplasmic fluid, and the cell periphery. We will compare the predicted dynamics to new experimental measurements that simultaneously capture spindle structure and dynamics, and cytoplasmic motions. Comparisons will be made between predicted and observed responses under physical, molecular, and genetic perturbations. Intellectual Merit: The proposed work will bring a new approach to modeling mitotic spindle dynamics and positioning. The integrated experimental and theoretical approach will enable new insights into the mechanisms of positioning and asymmetric cell division. The project will contribute to the broader efforts to understand the mitotic spindle and cell division, a long-standing fundamental problem in cell biology. This work will expand technical knowledge in cellular biology, biophysics, experimental technique, statistical physics, applied math, fluid dynamics, partial differential equations, and numerical analysis.