Bridging the Gap Between Molecular and Mechanical Control of Cell Morphogenesis

弥合细胞形态发生的分子和机械控制之间的差距

• 批准号: 8825693
• 负责人: Otger Campas
• 金额: $ 34.73万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8825693
• 关键词: Actins; Address; Affect; Algorithms; Animal Model; Antifungal Antibiotics; Bacteria; Biological Models; Case Study; Cell Shape; Cell Wall; Cells; Cereals; Chemicals; Couples; Coupling; Development; Drug Targeting; Elements; Event; Generic Drugs; Genetic Models; Genotype; Goals; Growth; Hybrids; Individual; Measures; Mechanics; Medicine; Microscopic; Modeling; Molecular; Molecular Biology; Morphogenesis; Partner in relationship; Phenotype; Plants; Process; Property; Research; Saccharomyces cerevisiae; Shapes; Time; Work; Yeasts; computer framework; drug development; fungus; improved; multi-scale modeling; public health relevance; research study; simulation

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.

描述（由申请人提供）：该提案的目的是通过整合细胞形态发生的分子和机械方面来获得对细胞如何建立和控制其形状的全球理解。这项研究将解决我们当前对形态发生的理解的主要差距，即细胞形状的分子控制和物理控制之间的断开。研究围墙细胞，例如植物，真菌和细菌细胞， 已经表明，细胞壁扩张和生长的力学严重影响形态发生。分子生物学研究提供了有关塑造细胞涉及的个体化学物种的有价值的信息，但是目前尚不清楚分子信息如何连接到时空中雕刻细胞的物理/机械过程，从而使基因型与形态表型之间的连接几乎不可能。为了弥合这一差距，我们提出了一项高度协调的努力，包括细胞壁力学模型，测量和扰动关键物理参数，例如新的细胞壁组装及其材料属性，以及多规模计算框架的开发，以将分子事件的随机仿真集成了与细胞极化元素的生长相结合的模拟元素的分子事件的随机模拟。具体而言，我们将：（1）开发一种酵母交配投影的多尺度模型，该模型将细胞内事件的动力学与细胞壁力学和生长结合在一起。 （2）实验表征酿酒酵母中交配投影尖端生长的机械和分子决定因素。我们将使用酿酒酵母中的交配投影的形成作为案例研究，因为酵母将遗传模型生物体的强度与尖端生长的简单性相结合，这是一种用于细胞形态发生力学的模型系统。 （3）开发一个通用的计算框架，以将细胞壁扩展的力学桥接到细胞内事件的动力学。这将需要算法，以偶联具有移动边界的区域上的物理和分子过程，空间随机模拟中肌动蛋白动力学的建模以及杂交介质/显微镜模拟。