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，但细胞如何协调探索其环境和向前运动仍然未知。 — 类似于飞机的机翼和尾翼，它们对于升力、稳定性和转向至关重要，就像副翼和方向舵对于飞机的操纵来说是必要的，但孤立起来是无效的，该项目将探索肌动蛋白网络子系统在引导和驱动细胞迁移方面的相互依赖性，该研究将确定每个子系统内的各个部分以及它们如何相互作用以产生基质引导的迁移的更广泛的影响。包括让高中生使用学生设计的纳米制造基质进行细胞运动挑战实验，并建立“The A-mazing Cell Races”网站来展示结果并让公众了解细胞生物学的动态。该项目的创新策略是强制实现单一细胞功能并识别产生该功能的部分，这是一种革命性的方法，用于研究无法使用传统生化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 ECM 的位置。广泛的研究表明，突起包含多个具有不同结构的肌动蛋白网络，但是，对每个网络在探测和向前运动中的作用的了解还很有限。然而，在受体与 ECM 结合之前，这些网络被认为不会与受体连接。该提案通过将肌动蛋白网络和 ECM 受体视为复杂的系统（一个集合体）来解决这些重大缺陷。然而，正如我们许多人小时候所学到的那样，他们把一些东西拆开来弄清楚它是如何工作的，最终得到了一盒无法组装在一起的零件，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消失时该项目将研究 ECM 引导的细胞迁移，作为一个由不可分离、分层、交互、动态 ECM 受体-肌动蛋白网络子系统组成的复杂系统，可调节探测和前向迁移。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使用 ECM 迷宫挑战细胞以参与多个子系统以应对复杂的挑战将定义子系统层次结构。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。