Understanding mitotic spindle positioning by integrated modeling and experiment

描述（由申请方提供）：细胞分裂期间形成有丝分裂纺锤体，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，分裂平面的位置和方向由纺锤体的位置和方向控制。然而，主轴定位的力机制是不好理解的。提出了两种备选模式。一个引起微管与细胞皮层的相互作用，另一个引起微管与细胞质的相互作用。我们的目标是发现哪种模型（如果不是两种） 通过使用C.早期胚胎项目团队具有生物物理理论、实验、数学建模和仿真方面的技能。这两种模型之间的一个本质区别是微管是否主动或被动地与细胞质相互作用，但考虑到系统的复杂性，很难单独用实验来区分。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，以及它们的组合，并将这些与实际流量的实验测量进行比较。详细的流体动力学相互作用还没有考虑到以前的建模纺锤体动力学，并需要新的方法，有效和准确地捕捉纺锤体微管相互作用，细胞质液，和细胞周边。我们将比较新的实验测量，同时捕获纺锤体结构和动力学，细胞质运动的预测动态。将在物理、分子和遗传扰动下预测和观察到的反应之间进行比较。智力优点：拟议的工作将带来一个新的方法来模拟有丝分裂纺锤体的动力学和定位。综合实验和理论的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，这是细胞生物学中长期存在的基本问题。这项工作将扩大在细胞生物学，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关于纺锤体和微管在细胞分裂和生物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点。

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.