Modeling mechanisms in cytokinesis, cell polarization and motility

项目概要/摘要 细胞分裂、建立极化方向和爬行移动的能力需要协调的 细胞骨架与细胞膜的相互作用，以及与细胞膜上组织的信号系统的相互作用， 膜。预测性数学和计算模型的发展面临的一个主要挑战， 这些亚细胞组织的机制解释了分子间的高度特异性相互作用， 水平导致涌现的集体行为。我们建议通过采用强大的 将分子与细胞尺度联系起来的计算和建模方法，与 实验学家致力于模型系统，（i）揭示重要的细胞生物学功能，（ii） 适用于定量方法。拟议的研究计划将解决机制， 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 在分裂酵母中，通过浓缩形成一条含有肌球蛋白的宽带膜结 和。这些模型将节点（大分子复合物）表示为单个单元， 能够伸展和拉动肌动蛋白。使用来自超分辨率实验的输入并应用粗- 颗粒生物物理建模和贝叶斯推理方法，我们建议模型的超微结构和 节点的动力学，这种组织如何影响它们捕获和拉动肌动蛋白丝的能力，以及 V型肌球蛋白的作用。我们将开发模型来研究膜传递如何在整个细胞中分布， 隔膜以及它如何与收缩环收缩和张力协调。B。细胞极化和ER organization.我们将研究Cdc 42/Ras 1系统如何建立具有不同空间分布的模式 GEF和GAP调节子的表达。将开发新的建模方法，以了解如何 内质网膜呈亚细胞分布在皮层片上，皮层片粘附在质膜上， 窗孔锚定到Eisosomes和内部管状网络，共同调节细胞极化。C.肌动蛋白 运动细胞的动力学我们将开发行动动力学和组织行为水平模型， 板状伪足，解释了它们的树突状网络结构、分布的周转、力的传递和 分支、切断和聚合的机械调节。与Watanabe集团合作 （京都大学），我们将测试这些模型，通过测量周转和流动附近的局灶性粘连与单 肌动蛋白和调节因子的分子成像。

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.