Modeling mechanisms in cytokinesis, cell polarization and motility

胞质分裂、细胞极化和运动的建模机制

基本信息

批准号：
10378767
负责人：
Dimitrios Vavylonis
金额：
$ 42.77万
依托单位：
LEHIGH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

项目摘要

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.

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细胞骨架与膜以及信号系统的相互作用膜。预测数学和计算模型发展的主要挑战亚细胞组织的这些机制正在解释分子间相互作用的高度特异性水平导致集体行为的出现。我们建议通过使用强大的解决方案来解决这种复杂性将分子与细胞尺度联系起来的计算和建模方法，与实验人员致力于模型系统（i）揭示重要的细胞生物学功能，并且（ii）适合定量方法。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.细胞分裂。我们之前已经模拟了收缩环如何在裂殖酵母中，通过缩合形成含有肌球蛋白的宽带膜结合节点和福明。这些模型代表节点，它们是大的大分子复合物，作为具有聚合和拉动肌动蛋白的能力。使用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，我们建议对超微结构和节点的动态，该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过程中分布隔膜及其如何与收缩环收缩和张力协调。 B. 细胞极化和 ER 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细胞膜上的 GEF 和 GAP 调节剂。将开发新的建模方法来了解如何 ER 膜亚细胞分布在附着于质膜的皮质片上，皮质片窗孔固定在胞质体和内部管状网络上，共同调节细胞极化。 C.肌动蛋白运动细胞的动力学。我们将开发肌动蛋白动力学和组织的丝级模型片状伪足解释了它们的树突网络结构、分布式周转、力传递和支化、断裂和聚合的机械调节。与渡边集团合作（京都大学），我们将通过测量单个粘着斑附近的营业额和流量来测试这些模型肌动蛋白和调节剂的分子成像。