Integrating Four-Dimensional Cell Migration Modeling with Quantitative Experiments

许多真核细胞能够移动，这种能力在许多生物过程中发挥重要作用，包括胚胎发生、发育、伤口愈合和病理性疾病，包括炎症和癌症转移癌症。这种运动发生在各种细胞外环境中，包括纤维细胞外基质（ECM）。ECM的生物物理特性，包括尺寸、硬度和限制程度，可以严重影响细胞的迁移，但其机制知之甚少。该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，该平台将适用于并可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产生的新颖和定量的实验数据相结合。具体而言，他们的实验将量化ECM中的细胞迁移，并仔细控制其特性，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过渡。项目活动将包括对高中生、本科生和研究生的培训，他们将直接参与拟议的研究。团队成员还将扩大与当地两所高中的现有合作，一所是普鲁斯特许学校，一所只接受来自弱势家庭学生的当地顶尖高中，另一所是克莱蒙特高中。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对象的数学模型，并创建可以解决细胞和纤维ECM之间相互作用的技术。研究团队将专注于细胞的动力学，从而实现4D（3D空间+1D时间）细胞迁移建模。该模型将基于相场描述，其避免了明确跟踪和参数化变形细胞膜的需要，其可以自然地并入细胞内信号传导通路，并且其可以容易地扩展以描述集体迁移。实验将量化ECM中的细胞迁移与仔细控制的属性，专注于ECM诱导的单一和集体迁移之间的过渡和单向和旋转迁移之间。实验结果将被纳入他们的模型，而建模将被用来生成实验测试的预测。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ECM特性如何调节单个与集体迁移; 2）开发受限迁移的数学模型，并确定细胞如何调节单向与旋转集体迁移。ECM相互作用。该奖项反映了NSF的法定使命，并被认为是值得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的支持。

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.