Collaborative Research: Multi-Scale Models and Quantitative Experiments of Red Blood Cells Transmigration through Inter-Endothelial Slits in the Spleen

合作研究：红细胞通过脾脏内皮间缝隙迁移的多尺度模型和定量实验

• 批准号: 1706571
• 负责人: Juan Carlos del Alamo
• 金额: $ 30.06万
• 依托单位: University of California-San Diego
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1706571&HistoricalAwards=false
• 关键词: Collaborative; Research; Multi; Scale; Models

CBET - 1706436/1706571PIs: Peng, Zhangli/del Alamo, Juan CarlosDuring their circulation through the spleen, red blood cells are challenged to squeeze through narrow slits between endothelial cells that are much smaller than the red blood cell itself. The squeezing motion leads to large red cell deformations and significant mechanical forces on the cells that can cause cell rupture. Aged or otherwise altered red blood cells become trapped and are removed from the circulation. The goal of this collaborative project is to understand the mechanics of red blood cell transmigration through narrow slits by a combination of experiments and high-fidelity numerical modeling. Microfluidic-based experiments will be used to measure the forces required for healthy and diseased red blood cells to move through slits with well-defined widths and geometries. A multi-scale computational model will be developed to fully characterize red blood cell transmigration through slits in the spleen. The results will show how transmigration depends on the geometrical and mechanical properties of the red blood cell and its environment from the molecular level to tissue level. This research may also contribute to knowledge about other important physiological processes, including inflammation and the metastatic spread of tumors, in which transmigration of cells through narrow slits plays an important role. Elements of this project will be adapted for hands-on demonstrations for high school students, and to excite youngsters and their parents about the importance and behavior of multi-component vesicles.Squeezing through narrow gaps requires significant mechanical forces and red blood cell deformations, which can lead to bilayer-cytoskeletal detachment, cell volume change, and cell rupture. Despite the importance of transmigration to red cell maintenance, there are no quantitative data available on the deformation and stress distributions of transmigrating red blood cells. A multiscale model of red blood cell transmigration will be developed that accounts explicitly for the lipid bilayer of the cell and its underlying cytoskeleton. A force microscopy technique will be used to measure the mechanical forces experienced by red blood cells while passing through slits of controlled size, stiffness and adhesiveness. Red blood cell deformation will be visualized as they pass through the slits, and the roles of microstructural components of the cells will be examined by pharmacological manipulations. Results from the experiments will be used to validate the computational model. The model in combination with experiment will be used to investigate how molecular alterations affect the filtration of RBCs in the spleen when the microstructural organization of the cells and the splenic environment are systematically altered. Results from these studies will be useful in understanding cellular deformation in physiological processes and in biomedical devices where cells undergo large deformations.

CBET-1706436/1706571 PI：彭、张立/德尔·阿拉莫、胡安·卡洛斯在通过脾循环期间，红细胞受到挑战，要从比红细胞本身小得多的内皮细胞之间的狭缝中挤出来。挤压运动会导致红细胞的大变形和细胞上显著的机械力，这可能会导致细胞破裂。老化或以其他方式改变的红细胞会被捕获，并从循环中移除。这个合作项目的目标是通过实验和高保真数值模拟相结合的方式来了解红细胞通过狭缝迁移的机制。基于微流体的实验将被用来测量健康和患病的红细胞通过具有明确宽度和几何形状的狭缝所需的力。将开发一个多尺度计算模型，以充分表征红细胞通过脾缝隙的迁移。结果将显示轮回如何依赖于红细胞的几何和机械性质以及从分子水平到组织水平的环境。这项研究还可能有助于了解其他重要的生理过程，包括炎症和肿瘤的转移扩散，在这些过程中，细胞通过狭缝的转运起着重要作用。这个项目的内容将被改编成高中生的动手演示，并让年轻人和他们的父母兴奋起来，让他们了解多成分囊泡的重要性和行为。挤压通过狭窄的缝隙需要巨大的机械力和红细胞变形，这可能导致双层细胞骨架分离、细胞体积变化和细胞破裂。尽管轮回对维持红细胞很重要，但关于轮回的红细胞的变形和应力分布，目前还没有定量的数据。将开发一个多尺度的红细胞迁移模型，明确说明细胞及其底层细胞骨架的脂类双层。力显微镜技术将被用来测量红细胞通过大小、硬度和粘附性受控的缝隙时所经历的机械力。当红细胞通过缝隙时，它们的变形将被可视化，细胞的微结构成分的作用将通过药物操作来检验。实验结果将用于验证计算模型。该模型与实验相结合，将用于研究当细胞的微结构组织和脾环境发生系统变化时，分子变化如何影响脾中红细胞的过滤。这些研究的结果将有助于理解细胞在生理过程中的变形以及在细胞发生大变形的生物医学设备中。