COMPUTATIONAL MODELING AND SIMULATION OF RECEPTOR-MEDIATED LEUKOCYTE ROLLING AD

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在组织损伤、外来因素攻击、甚至动脉粥样硬化的情况下，过去毛细血管中的白细胞归巢在机体的炎症反应中起着关键作用。通过一个复杂的多步骤过程，循环中的白细胞从流动的血液中被捕获到血管内皮细胞。在白细胞膜和内皮细胞上表达的选择素分子的介导下，白细胞进行缓慢滚动。随后，白细胞被整合素分子牢固地黏附，并通过内皮开窗转移到炎症或组织损伤的部位。选择素介导的白细胞缓慢滚动是至关重要的，因为它允许细胞‘搜索(靶点)。白细胞的滚动和粘连发生在血流的流体动力和细胞膜与内皮之间形成的受体/配体键的粘附力之间的平衡下。这个过程本质上是多尺度的--血浆的宏观运动提供了驱动力，而纳米级的粘附力提供了细胞的稳定性。为了了解在流体动力分散力作用下，选择素键如何调节细胞滚动，我们计划开发一种多尺度计算技术来研究流体流动条件下细胞/底物和细胞/细胞的黏附。计算方法将包括基于浸没边界方法的三维流体流动求解器(Navier-Stokes求解器)，以考虑细胞在与内皮细胞黏附过程中的变形。通过随机模拟将宏观流体动力学耦合到分子键的形成，其中选择素键的形成将用蒙特卡罗方法模拟。这项研究将阐明选择素键的细胞属性和生物物理参数如何在应激的流体动力学环境中促进细胞黏附。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Leukocyte homing in past-capillary vessels is critical in inflammatory response of the body during tissue injury, attack by foreign elements, or even in case of atherosclerosis. Through a complex multi-step process, circulating leukocytes are captured from the flowing blood in to the vascular endothelium. Mediated by selectin molecules expressed on the leukocyte membrane and on endothelial, leukocytes perform slow rolling. Subsequently, leukocytes are firmly adhered by integrin molecules, and transmigrate through endothelial fenestration to the sites of inflammation or tissue injury. The selectin-mediated slow rolling of leukocytes is crtical as it allows the cells to `search( for targeted sites. Leukocyte rolling and adhesion occurs under a balance between the hydrodynamic force of the blood flow, and the adhesion force of the receptor/ligand bonds formed between the cell membrane and the endothelium. The proceess is of multiscale in nature -- the macroscopic motion of the blood plasma provides the driving force, whereas the nanoscale adhesion force provide the stability of the cells. In order to understand how under the hydrodynamic dispersive forces, the selectin bonds mediate cell rolling, we plan to develop a multi-scale computational technique to address cell/substrate and cell/cell adhesion under hydrodynamic flowing condition. The computational method will consist of three-dimensional fluid flow solver (navier-Stokes solver) based on immersed boundary method to consider deformation of the cell during its adhesion to endothelium. The macroscopic fluid dynamics will be coupled to the molecular bond formation by stochastic simulation in which formation of selectin bonds will be simulated by Monte Carlo method. The research will elucidate how cellular properties, and biophysical parameters of selectin bonds promote cell adhesion under a stressful hydrodynamic environment.