CAREER: Impacts of Intracellular and Extracellular Hydraulic Environments on Mammalian Cell Migration in Confined Spaces

该学院早期职业发展奖将研究哺乳动物细胞在有限空间中的迁移如何受到细胞内外水力环境的影响。目前大多数关于哺乳动物细胞运动的流体动力学知识都是通过单独研究流体运动或与单一类型结构的流体相互作用而发展起来的。这一限制没有考虑流体和结构的相互作用如何影响细胞行为。这个项目将使用数学模型来破译受限细胞迁移中的这些耦合效应。该项目有望揭示水力学如何积极促进受限细胞迁移的新机制。这一结果将为研究液体在免疫反应、伤口愈合、组织再生和癌症转移等生物物理过程中的协同效应开辟新的途径。这些理论战略有望推动涉及多组件耦合的更广泛领域的建模技术，并促进受生物启发的水基系统的创造性设计。此外，这项计划将加强科学和工程教育，以部分翻转课堂的方式开发细胞力学的跨学科课程，通过建立关于细胞力学数学建模的支架式本科研究计划来培养未来的生物物理学家，并通过针对代表性不足的学生的外展计划来促进K-12跨学科教育。该项目的具体目标如下：(1)确定受限通道中额外细胞的存在如何影响细胞在受限通道中的迁移速度，(2)确定细胞在受限空间内利用非同步的核-细胞迁移模式的条件，并量化相关的能量效率，以及(3)阐明当细胞从开放空间变形到受限空间时，细胞核的双重作用。将开发基于生理学和连续介质力学的数学模型来研究这些目标。这些模型将针对一些依赖于细胞类型的特征，如膜蛋白表达水平，同时尽可能通用，以告知受限细胞迁移的典型特征。模型的结果和预测将从理论和实验上进行评估。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This Faculty Early Career Development (CAREER) award will study how mammalian cell migration in confined space is influenced by the hydraulic environment both inside and outside the cell. Most of the current knowledge on the fluid dynamics in mammalian cell motility has been developed by studying fluid motion alone, or fluid interaction with a single type of structure. This limitation does not consider how the interaction of the fluid and structure affects cell behavior. This project will use mathematical modeling to decipher these coupled effects in confined cell migration. This project is expected to reveal new mechanisms of how hydraulics can actively facilitate confined cell migration. The results will open new avenues of research in the synergistic effect of fluid in biophysical processes such as immune response, wound healing, tissue regeneration, and cancer metastasis. The theoretical strategies are expected to advance modeling techniques in broader areas that involve multi-component coupling and foster creative designs for bio-inspired, water-based systems. Additionally, this project will enhance science and engineering education via developing an interdisciplinary course on cell mechanics in a partially flipped-classroom approach, nurturing future biophysicists through establishing a scaffolded undergraduate research program on the mathematical modeling of cell mechanics, and promoting K-12 interdisciplinary education through outreach programs targeting underrepresented students.The specific objectives of this project are as follows: (1) identify how the velocity of a migrating cell in a confined channel is affected by the presence of an additional cell at the front, (2) determine the condition when cells utilize unsynchronized nucleus-cell migration mode within confined spaces and quantify the associated energy efficiency, and (3) elucidate the dual role of the nucleus when cells deform into confined spaces from open spaces. Physiology- and continuum mechanics-based mathematical models will be developed to study the objectives. The models will target a few cell type-dependent features such as membrane protein expression levels and at the same time be as generic as possible to inform typical features of confined cell migration. The model results and prediction will be theoretically and experimentally evaluated. The outcomes are projected to have a positive impact by advancing the knowledge of the active roles of hydraulics in confined cell migration and the techniques of modeling strategies.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.