Micromechanics of Red Blood Cells in Sickle Cell Disease

在本项目中，PI将通过引入粗粒分子动力学（CGMD），使用正常红细胞的双组分膜模型来模拟整个健康红细胞（RBC）。该模型将充分考虑膜骨架和磷脂双分子层。该模型将被扩展以模拟整个健康RBC。将获得静止健康RBC的特征，包括其双凹面形状和材料特性。此外，PI将通过创建聚合脱氧镰状血红蛋白（HbS）纤维的CGMD模型来模拟镰状RBC，并显示HbS纤维和膜之间的相互作用如何通过变形、膜损失和脱水导致生物力学特性和镰状RBC的各种形状。PI还将通过采用AFM测量正常和镰状RBC的局部和平均力位移响应（从中获得刚度），对模型进行实验验证。正常和镰状红细胞的平均和局部损失和储能模量也将通过主动显微流变学实验进行测量。同时，聚合的HbS的量和域将通过光学显微镜技术在测量机械性能的相同单元中确定。CGMD模拟的结果将与所提出的单细胞实验进行比较，以验证模型参数。推广活动将促进高中教师和学生的工程和科学知识，特别是将促进高中女生参与科学和技术。该教育计划将促进少数民族学生参与工程，并将提高学生对细胞力学多学科领域的兴趣。计算工具，实验装置和协议将通过一个免费访问的网站提供。

In this project, the PI will model the entire healthy red blood cell (RBC) by introducing a coarse-grain molecular dynamics (CGMD) using a two-component membrane model for normal RBCs. The model will fully count for both the membrane skeleton and the phospholipid bilayer. The model will be expanded to simulate the entire healthy RBC. The characteristics of a quiescent healthy RBC, including its biconcave shape and material properties, will be obtained. In addition the PI will model sickle RBCs by creating a CGMD model for polymerized deoxygenated sickle hemoglobin (HbS) fibers and show how the interaction between HbS fibers and the membrane results to the biomechanical properties and to the variety of shapes of sickle RBCs via deformation, membrane loss and dehydration. The PI will also experimentally validate the model by employong AFM to measure local and average force displacement responses for normal and sickle RBCs from which the stiffness will be obtained. The average and local loss and storage moduli of normal and sickle RBCs will also be measured via active microrheology experiments. Simultaneously, the amount and the domains of polymerized HbS will be determined via an optical microscopy technique in the same cells where the mechanical properties are measured. The results of the CGMD simulations will be compared with the proposed single cell experiments to validate the model parameters. The outreach activities will promote engineering and science in high school teachers and students and in particular they will advance the participation of high school girls in science and technology. The educational program will promote the involvement of minority students in engineering and it will increase the interest of students in the multidisciplinary field of cell mechanics. The computational tools, the experimental setup, and the protocols will be available via a freely accessible website.