Integrating Four-Dimensional Cell Migration Modeling with Quantitative Experiments

将四维细胞迁移模型与定量实验相结合

• 批准号: 1953469
• 负责人: Wouter-Jan Rappel
• 金额: $ 43.78万
• 依托单位: University of California-San Diego
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1953469&HistoricalAwards=false
• 关键词: Integrating; Four; Dimensional; Cell; Migration

Many eukaryotic cells are able to move, an ability that plays an important role in a number of biological processes, including embryogenesis, development, wound healing, and pathological diseases, including inflammation and cancer metastasis cancer. This motion occurs in a variety of extracellular environments, including fibrous extracellular matrix (ECM). The biophysical properties of the ECM, including dimension, stiffness, and degree of confinement, can critically affect the migration of cells but the mechanisms are poorly understood. The research team will develop mathematical models that describe cells as 3-dimensional (3D) objects with changing shapes and create techniques that can address cell interactions with fibrous ECM networks. They will create a modeling platform that will be applicable and extendable to a wide range of cell migration problems. They will then integrate their modeling with novel and quantitative experimental data that they will generate. Specifically, their experiments will quantify cell migration in ECM with carefully controlled properties, focusing on the ECM-induced transition between single and collective migration and between unidirectional and rotational collective migration. The project activities will include the training of high school, undergraduates, and graduate students who will be directly involved in the proposed research. The team members will also extend their existing collaboration with two local high school, the Preuss Charter School, a top local high school that accepts students only from disadvantaged families, and Clairemont High School. The goal of this project is to develop mathematical models that are able to describe cells as 3D objects with changing morphologies and create techniques that can address interactions between cells and fibrous ECMs. The research team will focus on the dynamics of cells, resulting in 4D (3D space+1D time) cell migration modeling. The model will be based on the phase-field description which avoids the need to explicitly track and parameterize the deforming cell membrane, which can naturally incorporate intra-cellular signaling pathways, and which can be easily extended to describe collective migration. The experiments will quantify cell migration in ECM with carefully controlled properties, focusing on the ECM-induced transition between single and collective migration and between unidirectional and rotational migration. The experimental results will be incorporated into their models while the modeling will be used to generate experimentally testable predictions. The specific aims for the project are 1) to develop a mathematical model for deformable 3D cells and determine how single vs. collective migration is regulated by ECM properties and 2) to develop a mathematical model for confined migration and determine how unidirectional vs. rotational collective migration is regulated by cell-ECM interactions.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.

许多真核细胞能够移动，这种能力在许多生物过程中起着重要作用，包括胚胎发生、发育、伤口愈合和病理疾病，包括炎症和癌症转移。这种运动发生在多种细胞外环境中，包括纤维细胞外基质（ECM）。ECM的生物物理特性，包括尺寸、刚度和约束程度，可以严重影响细胞的迁移，但其机制尚不清楚。研究小组将开发数学模型，将细胞描述为具有变化形状的三维（3D）物体，并创建可以解决细胞与纤维ECM网络相互作用的技术。他们将创建一个建模平台，该平台将适用于和扩展到广泛的细胞迁移问题。然后，他们将把他们的建模与他们将生成的新颖和定量的实验数据结合起来。具体来说，他们的实验将量化具有精心控制特性的ECM中的细胞迁移，重点关注ECM诱导的单一和集体迁移之间以及单向和旋转集体迁移之间的转变。项目活动将包括对直接参与拟议研究的高中生、本科生和研究生的培训。团队成员还将扩大与当地两所高中的合作，这两所高中是普鲁斯特许学校（Preuss Charter school）和克莱尔蒙特高中（Clairemont high school）。普鲁斯特许学校是当地顶尖的高中，只接受来自弱势家庭的学生。该项目的目标是开发能够将细胞描述为具有变化形态的3D物体的数学模型，并创建能够解决细胞与纤维性ecm之间相互作用的技术。研究团队将专注于细胞的动力学，从而建立4D （3D空间+1D时间）细胞迁移模型。该模型将基于相场描述，避免了明确跟踪和参数化变形细胞膜的需要，这可以自然地纳入细胞内信号通路，并且可以很容易地扩展到描述集体迁移。实验将量化具有严格控制特性的ECM中的细胞迁移，重点关注ECM诱导的单个和集体迁移之间以及单向和旋转迁移之间的转变。实验结果将被纳入他们的模型，而模型将用于生成实验可测试的预测。该项目的具体目标是1)开发可变形3D细胞的数学模型，并确定单个与集体迁移如何受ECM特性的调节；2)开发受限迁移的数学模型，并确定单向与旋转集体迁移如何受细胞-ECM相互作用的调节。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。