Collaborative Research: DMS/NIGMS 1: Simulating cell migration with a multi-scale 3D model fed by intracellular tension sensing measurements

这是印第安纳大学印第安纳波利斯分校和普渡大学之间的合作项目。细胞迁移在许多情况下起着重要作用，包括癌症转移、伤口愈合和免疫反应。例如，乳腺癌细胞迁移被认为是转移性骨或肺肿瘤的主要危险因素，伤口愈合中的成纤维细胞迁移在糖尿病和坏死性小肠结肠炎（危及生命的肠道伤口，影响10%的早产儿）中起作用。本项目旨在了解细胞迁移的内在特性，即细胞的内力如何响应周围、外部环境的特性并驱动细胞迁移。为了做到这一点，pi将开发一个新的迁移细胞的数学模型。该模型结合了预先存在的细胞迁移知识和细胞特性，以及可以测量亚细胞力的成像方法。该模型将在整个单元中产生力信息，而不仅仅是在测量位置。该模型加上适当的统计分析将有助于确定外部环境如何通过内部亚细胞力产生影响迁移。反过来，这将帮助我们更好地了解如何抑制（例如癌症）或促进（例如伤口愈合）细胞迁移，以改善患者的治疗效果。该项目将通过印第安纳大学印第安纳波利斯分校的NSF-DMS REU项目指导和培训来自多个学科的毕业生，来自缺乏研究机会的机构的本科生，以及通过美国化学学会项目SEED/STEM指导和培训社会经济条件不利的高中生。计划包括通过在几次会议上的演讲和小型研讨会，开放获取出版物，YouTube帖子，课堂模块，当地社区演讲（Science on Tap）以及针对代表性不足的高中生的STEM青年充实夏季项目进行推广。细胞迁移是由其细胞内的力量驱动，但主要是由细胞外的性质和扰动。为了了解细胞外特性如何决定内力以指导细胞迁移，pi计划实现三个具体目标：1)建立一个模型，整合实验测量的细胞内张力，并使用它们来建立整个细胞的力结构；2)使用该模型和实验测量来确定哪些亚细胞成分在细胞迁移中起主要作用；3)使用建模和实验来理解内力和细胞迁移对外部特性的响应。通过这种方法，pi将能够识别几种主要途径（外部属性到亚细胞组件到定向运动），通过这些途径，外部属性使用亚细胞力来指导迁移。在模型中，细胞将由一组相互连接的粘弹性弹簧来表示，这些粘弹性弹簧模拟了膜和其他亚细胞成分。该流将使用一种新的晶格-玻尔兹曼方法来模拟稳态斯托克斯流。流固耦合将采用浸入边界法进行建模。该模型将通过实验进行校准和验证。内部张力实验将使用成像方法和各种分子张力传感器来捕捉细胞内的力景观，特别是在病灶粘连，细胞骨架连接点和核膜处。外部环境的改变将包括细胞外基质刚度、趋化梯度和流动特性。相关性、敏感性和主成分分析将用于确定潜在的迁移途径。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。

This is a Collaborative Project between Indiana University Indianapolis and Purdue University. Cell migration plays a major role in many settings including cancer metastasis, wound healing, and the immune response. For example, breast cancer cell migration is considered a major risk factor for metastatic bone or lung tumors and fibroblast migration in wound healing has roles in diabetes and necrotizing enterocolitis (life-threatening intestinal wounds that affect 10% of premature babies). This project aims to understand the intrinsic properties of cell migration, i.e., how internal forces of a cell respond to the properties of the surrounding, external environment and drive cell migration. To do this, The PIs will develop a novel mathematical model of a migrating cell. The model combines pre-existing knowledge of cell migration and cell properties with an imaging method that can measure subcellular forces. The model will yield force information throughout the cell, not just at the measurement locations. Accompanying that model with appropriate statistical analysis will help identify how the external environment can effect migration via internal subcellular force generation. This, in turn, will help us better understand how to inhibit (e.g. cancer) or promote (e.g. wound healing) cell migration in order to improve patient outcomes. The project will mentor and train graduates from multiple disciplines, undergraduates from institutions lacking research opportunities through Indiana University Indianapolis’s NSF-DMS REU program, and socioeconomically disadvantaged high schoolers through the American Chemical Society Project SEED/STEM. Plans include outreach via presentations and minisymposia at several conferences, open-access publications, YouTube postings, in-class modules, local community presentations (Science on Tap), and the STEM Youth Enrichment Summer program for underrepresented high schoolers. Cell migration is driven by its intracellular forces but is mainly directed by extracellular properties and perturbations. To understand how extracellular properties determine internal forces to direct cell migration, the PIs plan to accomplish three specific aims: 1) Develop a model that integrates experimentally measured intracellular tensions and uses them to establish a force architecture throughout the cell, 2) Use that model and the experimental measurements to identify which subcellular components play major roles in cell migration, and 3) Use modeling and experiments to understand the response of internal forces and migration of the cell to the external properties. Through this approach the PIs will be able to identify several primary pathways (external properties to subcellular components to directed motion) by which external properties use subcellular forces to direct migration. In the model, the cell will be represented by a set of interconnected viscoelastic springs modeling the membrane and other subcellular components. The flow will be modeled using a novel lattice-Boltzmann approach for steady-state Stokes flow. Fluid-structure interaction will be modeled using the immersed boundary method. The model will be calibrated and validated using the experiments. The internal tension experiments will use imaging methods and various molecular tension sensors to capture the force landscape within a cell, particularly at focal adhesions, cytoskeletal junctures, and the nuclear envelope. The external environmental alteration will include the extracellular matrix stiffness, chemotactic gradient, and flow properties. Correlation, sensitivity, and principal component analyses will be used to identify potential migratory pathways.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.