Uncovering the Underlying Biophysical Mechanisms of Directed Cell Migration

揭示定向细胞迁移的潜在生物物理机制

• 批准号: 2345411
• 负责人: Catherine Galbraith
• 金额: $ 104.95万
• 依托单位: Oregon Health & Science University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-01-15 至 2027-12-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2345411&HistoricalAwards=false
• 关键词: Uncovering; Underlying; Biophysical; Mechanisms; Directed

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.

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都是至关重要的。尽管如此，细胞如何协调探测环境与向前运动仍然未知。该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，它们对升力、稳定性和转向至关重要。正如副翼和方向舵都是飞机机动所必需的，但在孤立情况下是无效的，本项目将探索肌动蛋白网络子系统在转向和动力细胞迁移中的相互依赖性。使用纳米制造的矩阵来指导细胞行为走向单一的迁移行为，该研究将确定每个子系统中的部分，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矩阵的细胞运动挑战实验，并建立“令人惊叹的细胞竞赛”网站来展示结果，并让公众参与细胞生物学的动态。该项目的创新策略是强迫单个细胞功能并识别创建该功能的部分，这是一种变革性的方法，可以研究使用传统生化或分子方法无法分离的复杂系统。细胞利用肌动蛋白为基础的突起探测ECM，寻找结合的位置，并形成锚点，将自己向前拉。大量研究表明，突起包含多个不同结构的肌动蛋白网络。然而，了解每个网络在探测和向前移动中的作用是有限的。如果没有诱导代偿效应，这些网络就不能被隔离，如果没有受体，它们就不能探测或结合ECM。然而，直到受体与ECM结合，这些网络才被认为与受体相连。这一建议通过考虑肌动蛋白网络和ECM受体作为复杂的系统，一个产生比其组成部分更多功能的部分的组装来针对这些显著的差距。然而，正如我们许多人在孩提时代学到的那样，当我们把某样东西拆开来弄清楚它是如何工作的，最终得到的是一盒无法重新组装起来的零件时，一些隐藏的随机性、层次结构或对功能至关重要的集体动态会在碎片被移除时消失。该项目将研究ECM引导的细胞迁移作为一个复杂的系统，该系统由不可分离的、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，这些子系统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对底物线索作出反应。挑战细胞，让多个子系统使用ECM迷宫来应对复杂的挑战，将定义每个选择的子系统行动层次，并允许使用图论来模拟细胞应对这些复杂的挑战。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。