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至关重要。尽管很重要，但细胞如何与向前运动进行探测其环境仍然未知。该项目将肌动蛋白细胞骨架网络和粘合剂受体视为不可或缺但独特的子系统 - 类似于飞机的机翼和尾巴，这对于升力，稳定性和转向至关重要。正如飞机的操纵所必需的，既然是孤立的，那么该项目也将探索肌动蛋白网络子系统在转向和动力电池迁移方面的相互依存关系。该研究使用旨在将细胞行为引向单个迁移行为的纳米制造物质，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。更广泛的影响包括使用学生设计的纳米制造物质与高中生进行细胞运动挑战实验，并建立“ A-Mazing Cell Races”网站以呈现结果，并以细胞生物学的动态吸引公众。该项目迫使单个细胞功能并确定创建该功能的部分的创新策略是研究复杂系统的一种变革性方法，该方法无法使用传统的生化或分子方法进行分离。细胞使用基于肌动蛋白的突起来探测ECM的绑定和形成锚以向前拉的位置。广泛的研究表明，蛋白质包含具有不同结构的多个肌动蛋白网络。但是，了解每个网络在探测和向前运动中的作用是有限的。没有诱导的补偿效应，无法隔离网络，并且它们不能在没有受体的情况下探测或结合ECM。但是，直到受体与ECM结合之前，网络才被认为与受体连接。该提案通过将肌动蛋白网络和ECM接收器视为复杂系统来针对这些显着差距，该系统的组合比其组件产生更多的功能。但是，正如我们许多人所学到的那样，他们把一些东西分开来弄清楚它是如何工作的，并最终得到了一盒无法放回的零件，当删除零件时，功能的一些隐藏的随机性，层次结构或集体动态必不可少。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，分层，交互式，动态的ECM受体 - 肌动蛋白网络子系统组成，该系统调节探测和正向迁移。使用纳米制造的ECM底物将识别子系统，并确定它们对细胞，亚细胞和单分子水平的底物线索的反应。挑战细胞以使用ECM迷宫来吸引多个子系统以应对复杂的挑战，将定义每种选择的子系统层次结构，并使使用图理论可以模拟这些复杂的挑战。该奖项反映了NSF的法定任务，并被认为是通过基金会的知识优点和广泛影响来评估的支持。