Bridging the Gap Between Molecular and Mechanical Control of Cell Morphogenesis

描述（由申请人提供）：本提案的目标是通过整合细胞形态发生的分子和机械方面，全面了解细胞如何建立和控制其形状。这项研究将解决我们目前对形态发生的理解中的一个主要空白，即细胞形状的分子和物理控制之间的脱节。对植物、真菌和细菌等有壁细胞的研究， 已经表明，细胞壁扩张和生长的机制对形态发生有重要影响。分子生物学研究已经提供了有关塑造细胞所涉及的单个化学物质的有价值的信息，但尚不清楚分子信息如何与在空间和时间上塑造细胞的物理/机械过程相联系，从而使基因型和形态表型之间的联系几乎不可能。为了弥合这一差距，我们提出了一个高度协调的努力，包括细胞壁力学模型，测量和扰动关键物理参数的实验，如新的细胞壁组装及其材料特性，以及多尺度计算框架的发展，以将控制细胞极化和生长的分子事件的随机模拟与粗-细胞壁膨胀力学的颗粒模型。具体而言，我们将：（1）开发酵母交配预测的多尺度模型，将细胞内事件的动力学与细胞壁力学和生长相结合。(2)通过实验表征S.啤酒。我们将利用S.酿酒酵母作为一个案例研究，因为酵母结合了遗传模式生物的优势与尖端生长的简单性，细胞形态发生机制的模型系统。(3)开发一个通用的计算框架，将细胞壁扩张的机制与细胞内事件的动力学联系起来。这将需要算法的物理和分子过程的耦合与移动边界的区域，空间随机模拟中的肌动蛋白动力学建模，和混合介观/微观模拟。

DESCRIPTION (provided by applicant): The goal of this proposal is to obtain a global understanding of how cells establish and control their shapes by integrating the molecular and mechanical aspects of cellular morphogenesis. This research will address a major gap in our current understanding of morphogenesis, namely the disconnect between the molecular and physical control of cell shape. Studies of walled cells, such as plant, fungal and bacterial cells, have shown that the mechanics of cell wall expansion and growth critically affect morphogenesis. Molecular biology studies have provided valuable information about the individual chemical species involved in shaping cells, but it is unclear how the molecular information is connected to the physical/mechanical processes that sculpt cells in space and time, rendering the connection between genotype and morphological phenotype virtually impossible. To bridge this gap, we propose a highly coordinated effort encompassing models of cell wall mechanics, experiments that measure and perturb key physical parameters such as new cell wall assembly and its material properties, and the development of a multi-scale computational framework to integrate the stochastic simulations of molecular events governing cell polarization and growth with finite element simulations of a coarse-grained model for the mechanics of cell wall expansion. Specifically, we will: (1) Develop a multiscale model of yeast mating projections that couples the dynamics of intracellular events to cell wall mechanics and growth. (2) Characterize experimentally the mechanical and molecular determinants of mating projection tip growth in S. cerevisiae. We will use the formation of mating projections in S. cerevisiae as a case study, because yeast combines the strengths of a genetic model organism with the simplicity of tip growth, a model system for the mechanics of cellular morphogenesis. (3) Develop a generic computational framework to bridge the mechanics of cell wall expansion to the dynamics of intracellular events. This will require algorithms for the coupling of physical and molecular processes on regions with moving boundaries, modeling of actin dynamics in spatial stochastic simulation, and hybrid mesoscopic/microscopic simulation.