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

合作研究：DMS/NIGMS 1：使用由细胞内张力传感测量提供的多尺度 3D 模型模拟细胞迁移

• 批准号: 2347957
• 负责人: Jing Liu
• 金额: $ 20万
• 依托单位: Purdue University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2347957&HistoricalAwards=false
• 关键词: Collaborative; Research; DMS; NIGMS; Simulating; Collaborative; Research; DMS; NIGMS; Simulating

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.

这是印第安纳大学印第安纳波利斯和普渡大学之间的合作项目。细胞迁移在许多环境中起着主要作用，包括癌症转移，伤口愈合和免疫响应。例如，乳腺癌细胞的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中具有作用（危及生命的肠道伤口，影响10％的早产儿）。该项目旨在了解细胞迁移的内在特性，即细胞的内部力如何应对周围，外部环境和驱动细胞迁移的特性。为此，PI将开发一个迁移细胞的新数学模型。该模型将对细胞迁移和细胞特性的先前存在的知识与可以测量亚细胞力的成像方法结合在一起。该模型将通过细胞产生力信息，而不仅仅是在测量位置。伴随该模型进行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，这将有助于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，以改善患者的结局。该项目将指导和培训来自多个学科的毕业生，来自印第安纳大学印第安纳大学NSF-DMS REU计划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/STEM通过美国化学学会项目/STEM的社会经济上的高中生。计划包括通过演讲进行外展活动和在几个会议上的迷你群，开放式出版物，YouTube帖子，课堂模块，当地社区演讲（Science On Tap）和STEM青年富有夏季计划的高中生。细胞迁移是由其细胞内力驱动的，但主要由细胞外特性和扰动引导。为了了解细胞外特性如何决定内部力直接导致细胞迁移，PIS计划完成三个特定的目的：1）开发一个模型，该模型整合了实验测量的细胞内紧张张力，并使用它们来建立力量架构，并在整个单元格中建立一个模型，2）使用模型和实验测量，以确定细胞迁移和实验的迁移和实验3），并实验了迁移和实验的模型，并实验3）外部属性。通过这种方法，PIS将能够识别几种主要途径（对定向运动的亚细胞组件的外部特性），外部特性使用亚细胞力来指导迁移。在模型中，该单元将由一组建模膜和其他亚细胞成分建模的互连粘弹性弹簧表示。该流将使用新型的晶格玻璃体方法对稳态stokes流进行建模。流体结构相互作用将使用浸没的边界方法进行建模。该模型将通过实验校准和验证。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获细胞内的力景观，尤其是在局灶性粘合剂，细胞骨架连接和核环境下。外部环境改变将包括细胞外基质刚度，趋化梯度和流动特性。相关性，灵敏度和主要成分分析将用于识别潜在的迁移途径。该奖项反映了NSF的法定任务，并通过使用基金会的知识分子优点和更广泛的影响评估标准来评估值得支持。