Mechanics of Intracellular Pathogens and Biomimetic Systems Propelled by Actin Comet Tails

摘要一些引起李斯特菌病、脑膜炎和气肠炎等疾病的病原菌劫持了受感染细胞的蛋白质机制，形成丝状肌动蛋白彗尾，推动它们进入这些细胞。对导致这一运动的作用力的物理理解可以提供一种手段来控制感染的传播，并设计仿生系统，将其应用于药物输送。这项提议的目的是开发定量模型来预测细丝水平的特性如何决定细菌和仿生货物的宏观运动。拟议的工作有两个主要主题。第一个主题是测量和分析各种肌动蛋白驱动的仿生系统的运动性，并研究肌动蛋白网络的结构和力学性质以及仿生系统的形状和大小对其轨迹的影响。第二个主题是建立一个基于力学的运动性模型，其中肌动蛋白彗星的尾巴是由肌动蛋白细丝的随机和负载依赖的生长组装而成的。如果成功，所提出的工作结果将使我们能够通过改变肌动蛋白网络的分子属性来定制仿生系统的运动，例如肌动蛋白网络的丝长和取向的统计分布、交联度和聚合动力学。由于肌动蛋白网络被普遍用于在细胞中产生机械力，阐明分子结构和微观运动之间的关系对于理解细胞运动、伤口愈合、丝状突起和形态发生也具有重要意义。这一项目的结果将纳入投资促进机构开发的关于计算方法和实验技术的课程。PIS将参与教师研究经验(RET)推广计划，并为初中和高中教师提供可在课堂上使用的软件模块和实验数据。

Abstract A number of pathogenic bacteria responsible for diseases like listeriosis, meningitis and gas-troenteritis hijack the protein machinery of the infected cells to form a filamentous actin comet tail that propels them within these cells. A physical understanding of the forces that lead to this motion can provide a means to control spreading of infections and to design biomimetic systems with applications in drug delivery. The objective of this proposal is to develop quantitative models to predict how the filament-level properties determine the macroscale motion of bacteria and biomimetic cargo. The proposed work has two main themes. The first theme is to measure and analyze the motility of various actin-propelled biomimetic systems and to study how structural and mechanical properties of actin networks and the shape and size of biomimetic systems influence their trajectories. The second theme focuses on the development of a mechanics-based model for motility where the actin comet tail is assembled by stochastic and load dependent growth of actin filaments.If successful, the results of the proposed work will allow us to tailor the motion of biomimetic systems by varying the molecular properties of the actin networks such as the statistical distributions of the filament lengths and orientations, degree of cross-linking and kinetics of polymerization. Since actin-based networks are ubiquitously used to generate mechanical forces in cells, elucidation of the relationship between molecular structure and microscopic motion will also have important implications for understanding cell motility, wound healing, filopodial extensions and morphogenesis. The results from this project will be included in the courses on computational methods and experimental techniques the PIs have developed. The PIs will participate in the Research Experience for Teachers (RET) outreach program and provide middle and high school teachers with software modules and experimental data that they can use in their classes.