CAREER: Fluid-structure interactions in cytoskeletal assemblies

细胞是一种由更小的机器组成的机械机器，它将化学能转化为力和运动。细胞力学是许多细胞过程的关键，包括细胞形状、细胞运动和细胞分裂。细胞机械结构的主要组成部分是细胞骨架，它是一个高度动态的微丝网络。细胞骨架细丝受到附着在其上并沿着其行走的分子马达的力而不断移动。这些运动在细胞内产生血流。这些诱导的流体结构（细丝）相互作用是细胞骨架力学的关键；然而，在以前的研究中，它们在很大程度上被忽略了。本研究的目的是利用计算机模拟和数学建模来深入了解流固相互作用和细胞流动在细胞骨架组织和力学中的作用。通过与大学的天文馆和科学中心（每年约有16万游客）合作，将研究和教育部分整合在一起，创造一种身临其境的虚拟现实体验，使游客可以缩小到细胞大小并了解细胞力学。该小组将为高中教师制定课程并举办讲习班，以便在课堂上有意义地实施这些活动。细胞骨架是一种动态的自组织的细丝（包括肌动蛋白细丝和微管）和浸泡在细胞质液中的运动蛋白的组合。细胞骨架是细胞对外部机械刺激的反应以及许多细胞内机械过程（包括细胞运动和细胞分裂）的关键。细胞质液与柔性细丝之间的非局部相互作用是决定细胞骨架瞬态结构和力学的关键。然而，在细胞骨架组装的计算研究中，这些流体-结构相互作用在很大程度上被忽略了。首席研究员最近开发了一个平台，用于模拟大型聚合柔性细丝在斯托克斯流及其相关流中的动力学。本提案的最终目标是利用这个计算平台来理解流体结构相互作用和细胞质流动对细胞骨架组装的组织和力学的影响。该研究分为三个相互关联和互补的目标。Aim 1和Aim 2的目的是发展对流体-结构相互作用作用的基本理解，这种作用较少依赖于生理细节。这是通过简化微管组件的体外重构的硅重述，以及研究来自马达蛋白的力（目的1）和（解）聚合（目的2）对微管组件的组织和流变学的影响来实现的。在Aim 3中，我们将光电子显微镜和粒子跟踪数据与模拟相结合，研究了秀丽隐杆线虫第一次细胞分裂过程中有丝分裂纺锤体的定位和组装。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The cell is a mechanical machine made of smaller machines that transform chemical energy to force and motion. Cell mechanics is key to many cellular processes, including cell shape, cell motility and cell division. The main component of cell's mechanical machinery is the cytoskeleton, which is a highly dynamic network of microscopic filaments. The cytoskeletal filaments are continuously moved by forces from molecular motors that attach to and walk along them. These movements generate flows inside the cell. These induced fluid-structures (filaments) interactions are key to the cytoskeleton mechanics; yet they have been largely ignored in previous studies. The purpose of this research is to use computer simulations and mathematical modelling to develop a deep understanding of the role of fluid-structure interactions and cellular flows on the cytoskeleton organization and mechanics. The research and educational component are integrated by partnering with the Planetarium and Science Center (approximately 160,000 annual visitors) at the university, to create an immersive Virtual Reality experience so that the visitors can shrink down to the cell size and learn about cell mechanics. The team will develop a curriculum and hold workshops for high school teachers for meaningful implementation of these activities in the classroom. The cytoskeleton is a dynamic self-organized assembly of filaments - including actin filaments and microtubules - and motor-proteins immersed in the cytoplasmic fluid. The cytoskeleton is key to the cell's response to external mechanical stimuli as well as many intracellular mechanical processes, including cell motility and cell division. The nonlocal interactions between the cytoplasmic fluid and the flexible filaments are key to determining the transient structure and mechanics of the cytoskeleton. Yet these fluid-structure interactions have been largely ignored in computational studies of cytoskeletal assemblies. The principal investigator has recently developed a platform for simulating the dynamics of large assemblies of polymerizing flexible filaments in Stokes flow and their associated flows. The ultimate goal of this proposal is to use this computational platform to understand the effect of fluid-structure interactions and cytoplasmic flows on the organization and mechanics of cytoskeletal assemblies. The research is divided into three connected and complimentary Aims. The purpose of Aim 1 and Aim 2 is to develop a fundamental understanding of the role of fluid-structure interactions that is less dependent on the physiological details. This is achieved by in silico recapitulation of simplified in vitro reconstitutions of microtubule assemblies, and studying the effect of forces from motor-proteins (Aim 1), and (de)polymerization (Aim 2) on the organization and rheology of microtubule assemblies. In Aim 3, light and electron microcopy and particle tracking data is combined with simulations to study the positioning and assembly of the mitotic spindle in the first cell division of Caenorhabditis elegans.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.