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讯的计算平台

• 批准号: 10707957
• 负责人: VICTOR H BAROCAS
• 金额: $ 18.46万
• 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/10707957
• 关键词: Achievement; Back; Behavior; Biological Assay; Biological Process; Cell Communication; Cell Separation; Cell model; Cell surface; Cells; Code; Collagen; Collagen Fiber; Collagen Type I; Communication; Computer Models; Computer software; Data; Disease; Elements; Environment; Feedback; Fiber; Fibroblasts; Gel; Health; Individual; 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 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.

项目摘要 我们建议开发一个名为Tractor的新型计算平台，以促进理论 与基质力学的复杂模型的细胞运动模型和细胞矩阵相互作用 和重组。拖拉机将通过提供链接来解决重大的技术差距 在细胞力学和基质力学之间，两者都经过了广泛的研究，但是 其协同相互作用仍未得到探索。对于这项概念验证研究， 矩阵将作为I型胶原纤维网络表示，如常用胶原蛋白 凝胶测定，以谐波键连接的半串联珠子模型。动作 该单元格将通过引入一组孤立的珠子（称为“拖拉机” - ）来建模。 （1）从细胞延伸，（2）附着在附近的胶原蛋白纤维上，（3）缩回回到细胞， 用它们拖动胶原蛋白，（4）释放胶原蛋白。过程的关键要素 是在第三步之后，胶原蛋白珠已与 拖拉机的作用将形成新的债券，从而产生多个报告的可塑性 胶原力学研究人员。新的债券形成引入了不可逆性 过程，因此在步骤（4）中发布的矩阵不会返回其前步 - （1）配置。作为 重复循环，该单元将能够诱导矩阵的大变形 每个拖拉机都会产生相对少量的运动。的关键特征 拖拉机平台，将在此初步研究中开发，但仅在其中实施 用于探索目的的最简单形式将是其灵活性，以适应不同的模型 细胞力学和基质力学和组成。拖拉机也将是计算 创新，利用开源LAMMPS软件的能量最小化功能； 这种功能通常用作分子动力学计算的前奏，将是 重新使用以提供拖拉机的有效，灵活的基础，并为长期分布提供 拖拉机代码给其他用户。本文提出的关键概念证明的里程碑是 基于公认的实验观察：（1）细胞的工作拖拉机模型 压实周围的基质，（2）细胞极化的工作拖拉机模型 各向异性胶原蛋白凝胶中的各向异性牵引力，（3） 多个细胞在胶原凝胶中机械相互作用。实现这些里程碑 将证明拖拉机框架的潜力，并将进一步的追求作为一个 用于细胞基质相互作用的理论研究的建模工具。