Understanding mitotic spindle positioning by integrated modeling and experiment

描述(申请人提供)：有丝分裂纺锤体在细胞分裂过程中形成，将染色体分离成子细胞。它是真核细胞正常分裂所必需的。在大多数细胞中，分割面的位置和方向由纺锤体的位置和方向控制。然而，主轴定位背后的力机制尚不清楚。已经提出了两种替代模型。一种是微管与细胞皮质的相互作用，另一种是与细胞质的相互作用。目标是发现哪种型号(如果不是两种型号)是 通过使用线虫早期胚胎的建模、模拟和实验进行更正。该项目团队拥有生物物理理论、实验、数学建模和模拟方面的技能。这两个模型的一个本质区别是微管与细胞质是主动还是被动相互作用，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相关的细胞质流动及其组合，并将这些与实际流动的实验测量进行比较。以前在纺锤体动力学建模中没有考虑到详细的流体动力学相互作用，因此需要新的方法来有效和准确地捕获相互作用的纺锤体微管、细胞质流体和细胞外围。我们将把预测的动力学与同时捕捉纺锤体结构和动力学以及细胞质运动的新的实验测量进行比较。将对物理、分子和遗传扰动下的预测响应和观测响应进行比较。智力价值：拟议的工作将带来一种新的方法来模拟有丝分裂纺锤体的动力学和定位。这种实验和理论相结合的方法将使人们能够对细胞定位和不对称分裂的机制有新的见解。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。这项工作将扩展细胞生物学、生物物理学、实验技术、统计物理、应用数学、流体力学、偏微分方程组和数值分析方面的技术知识。 公共卫生相关性：这项研究将有助于阐明和解决纺锤体和微管在细胞分裂和有机体发育中的作用和控制的基本生物学问题。该项目对医学和人类健康具有重要意义，因为纺锤体和微管是化疗药物的靶标。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This research will help illuminate and resolve fundamental biological issues on the role and control of the spindle and microtubules in cell division and organismal development. The project is significant for medicine and human health as the spindle and microtubules are targets for chemotherapeutic drugs.