CAREER: Multiscale investigation of cortical actin organization and dynamics

职业：皮质肌动蛋白组织和动力学的多尺度研究

• 批准号: 1554896
• 负责人: Adriana Dawes
• 金额: $ 44.74万
• 依托单位: Ohio State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1554896&HistoricalAwards=false
• 关键词: CAREER; Multiscale; investigation; cortical; actin

Cells rely on a mechanical structure called the cortex to maintain their shape and to respond to chemical and mechanical cues in the environment. The cortex, which lies just below the outer membrane of the cell, consists primarily of polymerized filaments of the protein actin. These actin filaments are cross-linked by a variety of proteins that can reorient and even move the filaments, making the cortex a highly dynamic structure. Despite the importance of the actin cortex for critical cell functions, it is not clear how small scale interactions give rise to large scale patterns and functions associated with the cortex. This project will use mathematical modeling to bridge disparate time and space scales associated with cortical actin dynamics, directly linking molecular level interactions to the emergence of cell level functional structures. For this project, novel models will be constructed that draw on a variety of mathematical approaches, including stochastic models which take into account infrequent interactions, and continuum models which can track the moving boundary of the cortex as well movement of proteins in time and space. The development and analysis of these biologically based models will result in an improved understanding of actin and its regulation in a cellular context. This research will also be leveraged to recruit and retain women in Science, Technology, Engineering, and Mathematics fields through the development of an integrated undergraduate course in mathematical modeling, with recruitment of students through a number of existing programs at Ohio State University, including Women in Mathematics and Science and Women in Engineering. Students involved in this project, and in the undergraduate course, will be exposed to real world mathematics applications and will interact with peers from other disciplines in a supportive interdisciplinary environment.Mathematical modeling is an ideal tool for the investigation of complex biological systems, where experimental techniques are not available or are not feasible. At the macro-scale level, systems of partial differential equations will be used to investigate the interplay between biochemical and mechanical actin dynamics, and the consequence of these dynamics on cell shape. Asymptotic analysis will be used to explicitly study the role of curvature in actin dynamics, and moving boundary simulations will be used to study changes in cell shape. At the mesoscale level, integro-differential equations, which use integral kernels to describe actin filament dynamics, will be used to study the formation of large scale actin filament patterns such as asters, vortices and aggregates. At the micro-scale level, stochastic individual-based models will be used to determine physical properties of the local actin meshwork and to determine under what conditions the actin meshwork behaves as a viscoelastic material. By enforcing consistency across multiple time and space scales in the proposed models, mechanisms that give rise to cellular structures will be revealed. Analysis and simulations of these models will present unique challenges leading to improvement of techniques in several areas of applied mathematics, including asymptotic analysis, moving boundary simulations, nonlocal model analysis, and stochastic simulations. The proposed models will be motivated and validated in a single experimental organism, avoiding complications from combining in vitro data with in vivo data from multiple organisms and cell types. The integrated computational and analytical models resulting from this research will increase our understanding of a fundamental protein that is critical for proper cell function.

细胞依靠一种叫做皮层的机械结构来维持它们的形状，并对环境中的化学和机械线索做出反应。皮层位于细胞外膜的正下方，主要由肌动蛋白的聚合丝组成。这些肌动蛋白丝被各种蛋白质交联，这些蛋白质可以重新定向甚至移动肌动蛋白丝，使大脑皮层成为一个高度动态的结构。尽管肌动蛋白皮质对于关键细胞功能的重要性，但尚不清楚小规模的相互作用如何产生与皮质相关的大规模模式和功能。该项目将使用数学建模来桥接与皮质肌动蛋白动力学相关的不同时间和空间尺度，直接将分子水平的相互作用与细胞水平功能结构的出现联系起来。在这个项目中，将利用各种数学方法构建新的模型，包括考虑到不频繁相互作用的随机模型，以及可以跟踪皮层移动边界以及蛋白质在时间和空间中移动的连续模型。这些基于生物学的模型的开发和分析将导致在细胞环境中的肌动蛋白及其调节的理解得到改善。这项研究也将被用来招募和保留妇女在科学，技术，工程和数学领域通过数学建模的综合本科课程的发展，通过在俄亥俄州州立大学，包括妇女在数学和科学和妇女在工程的一些现有的计划招募学生。参与这个项目的学生，在本科课程，将接触到真实的世界的数学应用，并将在支持跨学科的环境中与来自其他学科的同行进行互动。数学建模是复杂的生物系统，实验技术不可用或不可行的调查的理想工具。在宏观尺度上，偏微分方程系统将被用来研究生物化学和机械肌动蛋白动力学之间的相互作用，以及这些动力学对细胞形状的影响。渐近分析将被用来明确研究肌动蛋白动力学的曲率的作用，和移动边界模拟将被用来研究细胞形状的变化。在中尺度水平上，积分微分方程，它使用积分核来描述肌动蛋白丝动力学，将被用来研究大尺度肌动蛋白丝模式，如星状，漩涡和聚集体的形成。在微观尺度上，随机的基于个体的模型将被用来确定局部肌动蛋白网络的物理特性，并确定在什么条件下肌动蛋白网络表现为粘弹性材料。通过在所提出的模型中实施跨多个时间和空间尺度的一致性，将揭示产生细胞结构的机制。这些模型的分析和模拟将提出独特的挑战，导致应用数学的几个领域，包括渐近分析，移动边界模拟，非局部模型分析和随机模拟技术的改进。所提出的模型将在单个实验生物体中进行激励和验证，避免将体外数据与来自多种生物体和细胞类型的体内数据相结合的并发症。这项研究产生的综合计算和分析模型将增加我们对一种对细胞正常功能至关重要的基本蛋白质的理解。