Modeling mechanisms in cytokinesis, cell polarization and motility

项目摘要/摘要 细胞分裂、建立极化方向和爬行移动的能力需要协调 细胞骨架与膜的相互作用以及与组织的信号系统的相互作用 膜。发展预测数学和计算模型面临的一个主要挑战 亚细胞组织的这些机制是对分子间高度特异性相互作用的解释 水平导致了突发的集体行为。我们建议通过使用强大的 将分子尺度与细胞尺度联系起来的计算和建模方法，与 研究模型系统的实验者(I)揭示了重要的细胞生物学功能和(Ii)是 服从于量化的方法。拟议的研究计划将解决以下机制 胞质分裂、细胞极化和运动。A.胞质分裂。我们之前已经模拟了收缩环是如何 在分裂酵母中，通过缩合形成一条含有肌球蛋白的宽带膜结节。 和福明。这些模型将节点，即大分子复合体，表示为具有 聚合和拉动肌动蛋白的能力。使用来自超分辨率实验的输入，并应用粗略- 粒化生物物理建模和贝叶斯推理方法，我们提出了对超微结构和 节点的动态，这种组织如何影响它们捕获和拉动肌动蛋白细丝的能力，以及 V型肌球蛋白的作用。我们将开发模型来研究膜剂如何在整个体内分布 以及它如何与收缩环收缩和张力相协调。B.细胞极化与内质网 组织。我们将研究CDC42/RAS1系统如何建立具有不同空间分布的模式 全环基金和GAP调节剂在细胞膜上的作用。将开发新的建模方法来了解如何 ER膜以亚细胞形式分布在附着在质膜上的皮质薄片上， 窗孔固定在胞体和内部管状网上，共同调节细胞极化。C.肌动蛋白 运动细胞中的动力学。我们将开发微丝级别的肌动蛋白动力学和组织模型 解释了它们树枝状网络结构、分布的周转、强迫传递和 分枝、断链和聚合的机械调节。与渡边集团合作 (京都大学)，我们将通过测量局部粘连附近的周转和流动来测试这些模型 肌动蛋白和调节剂的分子成像。

Project Summary/Abstract The ability of cells to divide, establish a polarization direction, and move by crawling requires the coordinated interactions of the cytoskeleton with membranes as well as with the signaling system organizing on membranes. A major challenge for the development of predictive mathematical and computational models of these mechanisms of subcellular organization is accounting of how highly specific interactions at the molecular level lead to the emergent collective behavior. We propose to address this complexity by employing powerful computational and modeling methods linking molecular to cellular scales, in close collaboration with experimentalists working on model systems that (i) reveal important cell biological functions and (ii) are amenable to quantitative approaches. The proposed research program will address mechanisms in cytokinesis, cell polarization and motility. A. Cytokinesis. We have previously modeled how the contractile ring in fission yeast forms through the condensation a broad band of membrane-bound nodes containing myosin and formin. These models represented nodes, which are large macromolecular complexes, as single units with the ability to polymerize and pull actin. Using input from super-resolution experiments and applying coarse- grained biophysical modeling and Bayesian inference methods, we propose to model the ultrastructure and dynamics of nodes, how this organization impacts their ability to capture and pull actin filaments, as well as the role of type V myosin. We will develop models to study how membrane delivery is distributed across the whole septum and how it coordinates with contractile ring constriction and tension. B. Cell polarization and ER organization. We will study how the Cdc42/Ras1 system establishes patterns with distinct spatial distributions of GEF and GAP regulators on cell membrane. Novel modeling methods will be developed to understand how the ER membrane is distributed subcellularly on cortical sheets adhered to the plasma membrane, cortical fenestrae anchored to eisosomes and internal tubular networks, altogether regulating cell polarization. C. Actin dynamics in motile cells. We will develop filament-level models of actin dynamics and organization in lamellipodia that account for their dendritic network structure, distributed turnover, force transmission and mechanical regulation of branching, severing and polymerization. In collaboration with the Watanabe group (Kyoto University), we will test these models by measuring turnover and flows near focal adhesions with single molecule imaging of actin and regulators.