TRACTOR: A Computational Platform to Explore Matrix-Mediated Mechanical Communication among Cells

TRACTOR：探索细胞间基质介导的机械通信的计算平台

• 批准号: 10515967
• 负责人: VICTOR H BAROCAS
• 金额: $ 22.27万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10515967
• 关键词: Achievement; Address; Back; Behavior; Biological Assay; Biological Process; Cell model; Cell surface; Cells; Code; Collagen; Collagen Fiber; Collagen Type I; Collection; Communication; Computer Models; Computer software; Data; Disease; Elements; Environment; Feedback; Fiber; Fibroblasts; Gel; Health; Individual; Lead; Link; Measures; Mechanics; Mediating; Modeling; Motion; Pattern; Process; Property; Publishing; Reporting; Research Personnel; Sensory; Series; Side; System; Technology; Testing; Theoretical Studies; Theoretical model; Tissues; Traction; Work; base; cell behavior; cell motility; computational platform; computer framework; computer studies; experimental study; flexibility; innovation; molecular dynamics; network models; next generation; novel; open source; polarized cell; sensor; tool

PROJECT SUMMARY We propose to develop a novel computational platform, called TRACTOR, to couple theoretical models of cell motility and cell-matrix interaction with a sophisticated model of matrix mechanics and reorganization. TRACTOR will address a significant technology gap by providing a link between cell mechanics and matrix mechanics, both of which have been studied extensively but whose synergistic interplay remains largely unexplored. For this proof-of-concept study, the matrix will be represented as a network of type I collagen fibers, as in commonly-used collagen gel assays, modeled as a semiflexible string of beads connected by harmonic bonds. The action of the cell will be modeled by introducing a separate set of isolated beads - called "tractors" - that (1) extend from the cell, (2) attach to nearby collagen fibers, (3) retract back to the cell, dragging the collagen with them, and (4) release the collagen. A critical element of the process is that after the third step, collagen beads that have been brought into close contact by the action of the tractors will form new bonds, creating the plasticity reported by multiple researchers in collagen mechanics. The new bond formation introduces irreversibility to the process, so the matrix released in step (4) does not return to its pre-step-(1) configuration. As the cycle repeats, the cell will be able to induce large deformations of the matrix even though each individual tractor generates relatively small amounts of motion. A key feature of the TRACTOR platform, to be developed during this initial study but implemented only in its simplest form for exploratory purposes, will be its flexibility to accommodate different models of cell mechanics and matrix mechanics and composition. TRACTOR will also be computationally innovative, leveraging the open-source LAMMPS software's energy minimization functionality; this functionality, normally used as a prelude to molecular dynamics calculations, will be repurposed to provide an efficient, flexible base for TRACTOR and for long-term distribution of the TRACTOR code to other users. Key proof-of-concept milestones proposed herein are based on well-established experimental observations: (1) a working TRACTOR model of a cell compacting the matrix around it, (2) a working TRACTOR model of a cell polarizing and exerting anisotropic traction in an anisotropic collagen gel, and (3) a working TRACTOR model of multiple cells interacting mechanically within a collagen gel. Achievement of these milestones will demonstrate the potential of the TRACTOR framework and justify further pursuit of it as a modeling tool for theoretical studies of cell-matrix interaction.

项目概要 我们建议开发一种新颖的计算平台，称为 TRACTOR，以耦合理论 细胞运动和细胞-基质相互作用模型以及复杂的基质力学模型 和重组。 TRACTOR 将通过提供链接来解决重大技术差距 细胞力学和基质力学之间的关系，两者都已被广泛研究，但 其协同相互作用在很大程度上尚未被探索。对于这项概念验证研究， 基质将表示为 I 型胶原纤维网络，如常用的胶原蛋白 凝胶测定，建模为通过谐波键连接的半柔性珠串。行动 将通过引入一组独立的珠子（称为“拖拉机”）来模拟细胞的形状 (1) 从细胞延伸，(2) 附着到附近的胶原纤维，(3) 缩回细胞， (4)释放胶原蛋白。该过程的关键要素 就是第三步之后，已经被紧密接触的胶原蛋白珠 拖拉机的动作将形成新的键，从而产生多个报告所报告的可塑性 胶原蛋白力学研究人员。新债券的形成引入了不可逆转性 过程，因此步骤（4）中释放的矩阵不会返回到步骤（1）之前的配置。作为 循环重复，细胞将能够引起基质的大变形，即使 每台拖拉机产生相对较小的运动量。该产品的一个关键特点是 TRACTOR 平台，将在初步研究期间开发，但仅在其 出于探索目的的最简单形式，将是其适应不同模型的灵活性 细胞力学和基质力学和组成。 TRACTOR 也将通过计算 创新，利用开源 LAMMPS 软件的能源最小化功能； 该功能通常用作分子动力学计算的前奏，将 重新调整用途，为 TRACTOR 和长期分销提供高效、灵活的基础 将 TRACTOR 代码发送给其他用户。本文提出的关键概念验证里程碑是 基于完善的实验观察：(1) 细胞的工作 TRACTOR 模型 压实周围的矩阵，(2) 细胞极化和施加作用的有效 TRACTOR 模型 各向异性胶原凝胶中的各向异性牵引，以及 (3) 工作 TRACTOR 模型 多个细胞在胶原凝胶内机械相互作用。这些里程碑的实现 将展示 TRACTOR 框架的潜力，并证明进一步追求它作为一个 用于细胞-基质相互作用理论研究的建模工具。