Uncovering the Underlying Biophysical Mechanisms of Directed Cell Migration

基质引导的细胞迁移是组织形成的基础，其失调在各种疾病中起着至关重要的作用。尽管这很重要，但细胞如何协调探测它们的环境和向前运动仍然是未知的。该项目将肌动蛋白细胞骨架网络和黏附受体作为完整但不同的子系统进行研究--类似于飞机的机翼和尾翼，它们对升力、稳定性和操纵性至关重要。就像副翼和方向舵都是飞机机动所必需的，但单独使用是无效的，这个项目将探索肌动蛋白网络子系统在引导和推动细胞迁移方面的相互依赖。这项研究使用旨在引导细胞行为向单一迁移行为的纳米碎片矩阵，将确定每个子系统中的各个部分，以及它们如何相互作用来创建矩阵引导的迁移。更广泛的影响包括让高中生参与细胞运动性挑战实验，使用学生设计的纳米碎块基质，以及建立“A迷宫细胞竞赛”网站来展示结果并让公众参与细胞生物学的动态。该项目的创新战略是强制单一细胞功能并识别产生该功能的部分，这是研究无法使用传统生化或分子方法分离的复杂系统的一种变革性方法。细胞使用基于肌动蛋白的突起来探测细胞外基质，寻找结合的地方，并形成锚点，将自己拉向前方。大量研究表明，突起中含有多个不同结构的肌动蛋白网络。然而，对每个网络在探测和向前移动中的作用的理解一直是有限的。如果不引起代偿效应，这些网络就不能被隔离，它们也不能在没有受体的情况下探测或结合ECM。然而，在受体与细胞外基质结合之前，这些网络被认为不会与受体相连。这项提议针对这些显著的差距，将肌动蛋白网络和细胞外基质受体视为复杂的系统，即产生比其组件更多功能的部件的组装。然而，就像我们中的许多人在孩提时代就学会了将某个东西拆开以弄清楚它是如何工作的，最终得到的是一盒无法组装的部件，当部件被移除时，一些隐藏的随机性、层级或功能所必需的集体动力就消失了。本项目将研究ECM引导的细胞迁移作为一个复杂的系统，它由不可分离的、分层的、交互的、动态的ECM受体-肌动蛋白网络子系统组成，这些子系统调节探测和前向迁移。使用纳米级ECM底物将识别子系统，并确定它们如何在细胞、亚细胞和单分子水平上对底物提示做出反应。使用ECM迷宫挑战细胞参与多个子系统以应对复杂的挑战，将定义每个选择的子系统行动层次，并能够使用图论对细胞导航这些复杂挑战进行建模。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Matrix-guided cell migration is fundamental to tissue formation, and its dysregulation is crucial in various diseases. Despite this importance, how cells coordinate probing their environment with forward movement remains unknown. This project examines actin cytoskeletal networks and adhesion receptors as integral yet distinct subsystems — akin to an airplane’s wings and tail, which are critical for lift, stability, and steering. Just as both the ailerons and rudder are necessary for an airplane’s maneuvering yet are ineffective in isolation, this project will explore the interdependence of actin network subsystems in steering and powering cell migration. Using nanofabricated matrices designed to direct cellular behavior towards single migration behaviors, the study will identify the parts within each subsystem and how they interact to create matrix-guided migration. The broader impacts include engaging high school students in cell motility challenge experiments using student-designed nanofabricated matrices and establishing ‘The A-mazing Cell Races’ website to present the results and engage the public with the dynamics of cell biology. The project’s innovative strategy of forcing a single cellular function and identifying the parts that create the function is a transformative approach to studying complex systems that cannot be separated using traditional biochemical or molecular approaches. Cells use actin-based protrusions to probe the ECM for places to bind and form anchors to pull themselves forward. Extensive studies have revealed that protrusions contain multiple actin networks with different structures. However, understanding each network’s role in probing and forward movement has been limited. The networks cannot be isolated without inducing compensatory effects, and they cannot probe or bind ECM without receptors. Yet, the networks are not thought to connect to receptors until the receptors bind to ECM. This proposal targets these significant gaps by considering actin networks and ECM receptors as complex systems, an assembly of parts that produces more functionality than its components. However, as many of us learned as children who took something apart to figure out how it worked and ended up with a box of parts that could not be put back together, some hidden randomness, hierarchy, or collective dynamic essential for functionality disappears when pieces are removed. This project will study ECM-guided cell migration as a complex system composed of non-separable, hierarchical, interactive, dynamic ECM receptor–actin network subsystems that regulate probing and forward migration. Using nanofabricated ECM substrates will identify the subsystems and determine how they respond to substrate cues at the cellular, sub-cellular, and single-molecule levels. Challenging the cells to engage multiple subsystems to navigate complex challenges using ECM mazes will define the subsystem hierarchy of action for each choice and enable the use of graph theory to model cells navigating these complex challenges.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.