CAREER: Predictive Multiscale Modeling of Cell Migration through Pores between Endothelial Cells

该学院早期职业发展（CAREER）奖将支持使用计算机模拟研究内皮细胞之间孔的细胞迁移的研究。 它的动机是我们体内每时每刻都发生的一个迷人而关键的过程：细胞挤压比自身小得多的毛孔。例如，8 μm左右的红细胞经常通过脾脏中0.5 μm左右的内皮孔挤压。这是他们定期的“体能测试”，它会破坏疟疾和血液疾病中的衰老细胞和病变细胞。另一个例子是嗜中性粒细胞，最丰富的白色血细胞，它通过挤压血管壁中的内皮孔而退出循环以对抗组织中的感染。在癌症中，循环肿瘤细胞也通过这些孔挤压到远处器官中转移，这是癌症死亡率的主要贡献者。为了挤出如此狭窄的孔，所有这些细胞都必须经历极端的机械变形。细胞内分子结构的微小变化对细胞的存活具有重要影响。在这个项目中，先进的计算机模拟将被应用于预测细胞的不同成分如何影响其通过小孔的能力。这项研究还将得到基于课程开发的教育和推广计划的补充，张拉整体结构的动手构建，以及一个细胞挤压演示器，以激励K-12学生追求STEM职业。研究目标是通过多尺度建模及其与实验数据的整合来揭示细胞跨内皮迁移（TEM）的生物力学和机械生物学。虽然已经进行了大量的实验来研究细胞的TEM，但在没有数学建模的帮助下，实现定量理解已被证明是具有挑战性的。不幸的是，有有限的TEM预测数学模型，由于其复杂性和多尺度的性质。为了应对这一挑战，该研究将采用多尺度建模方法，并整合实验数据来研究三种细胞类型的TEM：红细胞，中性粒细胞和肿瘤细胞。具体而言，研究目标包括：（i）研究脾脏机械过滤期间成熟和未成熟红细胞的TEM;（ii）研究肺毛细血管床炎症反应期间中性粒细胞的TEM;（iii）研究远处器官癌症转移期间肿瘤细胞核的TEM。该项目将推进我们对TEM的基本理解，并为细胞的生物力学和机械生物学等广泛的生物医学问题提供有价值的见解。该奖项反映了NSF的法定使命，并通过使用基金会的智力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 Faculty Early Career Development (CAREER) award will support research that will study the cell migration through pores between endothelial cells using computer simulations. It is motivated by a fascinating and crucial process happening in our body every moment: a cell squeezes through pores much smaller than itself. For example, red blood cells around 8 μm, frequently squeeze through endothelial pores around 0.5 μm in our spleens. This is their regular ‘physical fitness test’, which destroys aged cells and diseased cells in malaria and blood disorders. Another example is the neutrophil, the most abundant white blood cell, which exits the circulation to fight infections in the tissues by squeezing through endothelial pores in the blood vessel walls. In cancer, circulating tumor cells also squeeze through these pores to metastasize in distant organs, which is the major contributor to cancer mortality. To squeeze through such narrow pores, all these cells have to experience extreme mechanical deformation. Slight changes of molecular structures in the cell would have significant consequence on the cell’s survival. In this project, advanced computer simulations will be applied to predict how different components of the cell affect its ability to pass through small pores. This research will also be complemented by educational and outreach programs based on curriculum development, hands-on construction of tensegrity structures, and a cell squeezing demonstrator to inspire K-12 students to pursue STEM careers. The research goal is to reveal the biomechanics and mechanobiology of transendothelial migration (TEM) of cells by multiscale modeling and its integration with experimental data. Although extensive experiments have been conducted to study TEM of cells, achieving a quantitative understanding has proven challenging without the aid of mathematical modeling. Unfortunately, there are limited predictive mathematical models of TEM due to its complex and multiscale nature. To address this challenge, the research will adopt a multiscale modeling approach and integrate experimental data to investigate TEM of three cell types: red blood cells, neutrophils, and tumor cells. Specifically, the research objectives include: (i) study TEM of mature and immature red blood cells during mechanical filtration in spleens; (ii) study TEM of neutrophils during inflammation response in lung capillary beds; (iii) study TEM of a tumor cell nucleus during cancer metastasis in distant organs. This project will advance our fundamental understanding of TEM and contribute valuable insights into a wide range of biomedical problems such as biomechanics and mechanobiology of cells.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.