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至关重要。 尽管如此重要，细胞如何协调探测它们的环境与向前运动仍然是未知的。 本项目将肌动蛋白细胞骨架网络和粘附受体作为完整而独特的子系统进行研究-类似于飞机的机翼和尾翼，这对升力，稳定性和转向至关重要。就像副翼和方向舵对于飞机的机动是必要的，但在孤立的情况下是无效的一样，这个项目将探索肌动蛋白网络子系统在操纵和驱动细胞迁移中的相互依赖性。使用纳米制造的矩阵，旨在指导细胞行为向单一迁移行为，该研究将确定每个子系统内的部分，以及它们如何相互作用，以创建矩阵引导的迁移。 更广泛的影响包括让高中生参与使用学生设计的纳米制造基质的细胞运动挑战实验，并建立“The A-Mazing Cell Races”网站，以展示结果并让公众参与细胞生物学的动态。 该项目的创新策略是强制单一细胞功能并识别产生功能的部分，这是一种变革性的方法来研究无法使用传统生物化学或分子方法分离的复杂系统。细胞使用基于肌动蛋白的突起来探测细胞外基质以寻找结合的地方并形成锚点以将自己向前拉。 大量的研究表明，突起包含多个具有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是有限的。 在不诱导补偿效应的情况下不能分离网络，并且它们不能探测或结合没有受体的ECM。然而，这些网络被认为在受体与ECM结合之前不会与受体连接。该提案通过将肌动蛋白网络和ECM受体视为复杂系统来瞄准这些重大差距，这些复杂系统是一个部件的组装，其功能比其组件更多。 然而，正如我们中的许多人在孩提时代所学到的那样，当我们把某个东西拆开来弄清楚它是如何工作的，结果却得到了一个无法重新组装起来的零件盒，当零件被拆除时，一些隐藏的随机性，层次结构或对功能至关重要的集体动力就会消失。 本项目将研究ECM引导的细胞迁移作为一个复杂的系统，由不可分离的，分层的，相互作用的，动态的ECM受体-肌动蛋白网络子系统组成，调节探测和向前迁移。 使用纳米制造的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响应底物线索。 将细胞与多个子系统结合，使用ECM迷宫导航复杂的挑战，将为每个选择定义子系统的行动层次，并允许使用图论来模拟细胞导航这些复杂的挑战。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值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.