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

职业：通过内皮细胞之间的孔进行细胞迁移的预测多尺度建模

• 批准号: 2339054
• 负责人: Zhangli Peng
• 金额: $ 53.95万
• 依托单位: University of Illinois at Chicago
• 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: 2024-08-01 至 2029-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2339054&HistoricalAwards=false
• 关键词: CAREER; Predictive; Multiscale; Modeling; Cell

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.

该学院早期职业发展（CAREER）奖将支持利用计算机模拟研究细胞通过内皮细胞之间的毛孔迁移的研究，其动机是我们体内每时每刻都发生着一个令人着迷的关键过程：细胞挤过更小的毛孔。例如，8μm左右的红细胞经常挤过我们脾脏中0.5μm左右的内皮孔，这是它们的常规“体能测试”，它会破坏衰老的细胞和细胞。另一个例子是中性粒细胞，这是最丰富的白细胞，它通过挤压血管壁的内皮孔而退出循环，以抵抗组织中的感染。在癌症中，循环肿瘤细胞也会挤压。通过这些孔隙转移到远处的器官，这是癌症死亡的主要原因。为了挤过如此狭窄的孔隙，所有这些细胞都必须经历细胞内分子结构的轻微变化。在该项目中，将应用先进的计算机模拟来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、双手的教育和推广计划的补充。 -张拉整体结构的构建和细胞挤压演示器，以激励 K-12 学生从事 STEM 职业研究目标是通过揭示细胞跨内皮迁移 (TEM) 的生物力学和力学生物学。尽管已经进行了广泛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，由于 TEM 的复杂性和预测性，其预测数学模型有限。为了应对这一挑战，该研究将采用多尺度建模方法和实验数据来研究红细胞、中性粒细胞和肿瘤细胞这三种细胞的 TEM。成熟红色和未成熟红色(ii) 研究肺毛细血管床炎症反应期间的中性粒细胞的 TEM；(iii) 研究远处器官癌症转移期间肿瘤细胞核的 TEM。对细胞生物力学和细胞力学生物学等广泛的生物医学问题提出了宝贵的见解。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力优势进行评估，被认为值得支持以及更广泛的影响审查标准。