Simulation of Leukocyte Adhesion Cascade: Effects of Cell Deformation and Hydrodynamic Interactions between Cells

摘要提案编号： CTS-0625599主要制造商：K. Sarkarinstitution： 白细胞粘附级联的模拟：细胞变形和细胞间流体动力学相互作用的影响 白细胞（白色血细胞）从毛细血管后血流向感染部位的迁移是人体炎症反应的关键步骤。迁移过程涉及一系列白细胞-血管相互作用，称为白细胞粘附级联（LAC）。 级联反应中的每一步（白细胞边集、滚动、牢固粘附和最终的迁移）不仅涉及分子水平的化学和信号事件，而且涉及流体和界面运动、形状演变和细胞-细胞相互作用。这项资助的目标是开发一个全面的计算模型，并模拟白细胞粘附级联。 重点是对滚动过程中细胞变形和细胞-细胞相互作用的流体动力学效应的系统研究，以及当白细胞从内皮细胞连接处挤出时级联的迁移步骤的模型的开发。 目前的模型大多集中在局部分子粘附的物理化学，忽略了细胞变形和流体力学。血细胞的流动和变形是调节粘附级联的重要方面。 具体目标之一是开发一个全面的3D模型粘弹性细胞膜和分子结合，包括表面和大量的细胞流变学，并通过细胞连接和分子结合的白细胞的迁移。这个计算平台将发展的招聘和随后的白细胞迁移到发炎组织，这几乎发生在每一个器官的关键理解。 它将有助于开发用于诊断和治疗免疫缺陷和炎症相关疾病的改进方法，包括动脉粥样硬化和类风湿性关节炎。根据这项补助金，我的本科生和研究生将接受生物学和力学的非传统跨学科界面的培训。PI已经与摩根州立大学（HBCU）的合作者建立了联系，以确定有才华的本科生研究实习，并培养他们在特拉华州大学的研究生学习。

ABSTRACTPROPOSAL NO.: CTS-0625599PRINCIPAL INVESTIGATOR: K. SARKARINSTITUTION: U OF DELAWARESimulation of Leukocyte Adhesion Cascade: Effects of Cell Deformation and Hydrodynamic Interactions between Cells The migration of leukocytes (white blood cell) from post capillary blood stream to the site of infection is the key step in human body's inflammation responses. The migration process involves a sequence of leukocyte-blood-vessel interactions called the leukocyte adhesion cascade (LAC). Each step in the cascade (leukocyte margination, rolling, firm adhesion and final transmigration) involves not only the chemical and signaling events at the molecular level, but also the fluid and interface motion, shape evolution and cell-cell interactions. The goal of this grant is to develop a comprehensive computational model and to simulate the leukocyte adhesion cascade. The focus is on a systematic investigation of the hydrodynamic effects of cell deformation and cell-cell interactions in the rolling process and development of a model of the transmigration step of the cascade when the leukocyte squeezes out of the endothelial cell junctions. Current models are mostly focused on the physical chemistry of local molecular adhesion, neglecting the cell deformation and hydrodynamics. The flow and deformation of blood cells are important aspects regulating the adhesion cascade. Among the specific objectives is to develop a comprehensive 3D model for viscoelastic cells with membrane and molecular bindings, including the surface and bulk rheology of cells, and transmigration of leukocyte through cell junctions and molecular bindings. This computational platform will develop critical understanding of the recruitment and subsequent emigration of leukocytes into inflamed tissue, which occurs virtually in every organ. It will help develop improved methodologies for diagnosis and treatment of immunodeficiency and inflammation related diseases, including atherosclerosis and rheumatoid arthritis. Under this grant ME undergraduate and graduate students will be trained in the non-traditional cross-disciplinary interface of biology and mechanics. The PI has established a link with a collaborator in Morgan State University (an HBCU) to identify talented undergraduate research internships and to groom them for graduate study at the University of Delaware.