Vascular Relations of Blood Cells and Proteins

本项目的主题是力学、化学和流体动力学的相互关系，作为正常和病理外周血管功能，特别是炎症反应的潜在机制。五个项目参与了协同研究，旨在揭示外周血管正常和病理现象的基本机制，重点关注中性粒细胞-内皮细胞的相互作用。项目1、2、3和4具有共同的重点，并采用互补的方法来理解是什么控制整合素介导的中性粒细胞附着和迁移。特别强调的是将在体外观察到的行为（项目1、2和3）与体内临床相关事件（项目2和4）联系起来，在那里我们可以获得对粘附调节机制的精确理解。项目1使用定量模型和分子方法来了解趋化因子刺激与流中整合素激活和细胞固定化之间的信号事件，以及中性粒细胞爬行过程中力产生的实验（与项目2和项目3）。项目2使用分子方法来了解整合素在体内和体外迁移细胞的不同区域是如何被调节的。项目3利用单细胞实验揭示分子扩散和表面形貌如何影响粘附和细胞爬行的启动，并表征导致整合素亲和力和亲和度变化的信号通路动力学。项目4侧重于体内白细胞-内皮相互作用的机制，重点是粘附分子表达异质性的功能后果，以及白细胞连接引发的内皮细胞（EC）信号事件。项目5使用计算和实验方法来研究与细胞捕获相关的机制，特别是多粒子流体动力学和剪切应力可能影响细胞捕获和细胞激活的方式（与项目1和项目4）。除了计算研究以确定异常细胞几何形状对细胞捕获的影响。项目5和项目3正在探索通过g蛋白偶联受体影响l -选择素脱落和中性粒细胞对激动剂反应的机械转导机制。

The theme of this program project is the inter-relation of mechanics, chemistry and hydrodynamics as underlying mechanisms in normal and pathological peripheral vascular function, particularly the inflammatory response. Five projects are engaged in synergistic studies designed to reveal fundamental mechanisms underlying both normal and pathological phenomena in the peripheral vasculature with a central focus on neutrophil-endothelial interactions. Projects 1, 2, 3 and 4 have a common focus and employ complementary approaches to understand what governs integrin-mediated neutrophil attachment and migration. A particular emphasis is to relate behaviors observed in vitro (Projects 1, 2 and 3), where we can obtain precise understanding of regulatory mechanisms of adhesion, to clinically relevant events in vivo (Projects 2 and 4). Project 1 uses quantitative models and molecular approaches to understand signaling events connecting chemokine stimulus to integrin activation and cell immobilization in flow, as well as experiments on force generation during neutrophil crawling (with Projects 2 and 3). Project 2 uses molecular approaches to learn how integrin affinity is regulated in distinct regions of migrating cells both in vitro and in vivo. Project 3 uses single cell experiments to reveal how molecular diffusion and surface topography affect adhesion and the initiation of cell crawling, and to characterize the dynamics of signaling pathways leading to changes in integrin affinity and avidity. Project 4 focuses on the mechanisms underlying leukocyte-endothelial interaction in vivo, with emphasis on the functional consequences of heterogeneities in adhesion molecule expression, and signaling events in endothelial cells (EC) initiated by leukocyte ligation. Project 5 uses both computational and experimental approaches to study mechanisms related to cell capture, particularly with respect to ways that multiparticle hydrodynamics and shear stress may affect cell capture and cell activation (with Projects 1 and 4). In addition to computational studies to determine consequences of abnormal cell geometry on cell capture. Project 5, with Project 3, is exploring mechanotransduction mechanisms affecting L-selectin shedding and neutrophil response to agonists via G-protein coupled receptors. Peripheral vascular dysfunction is integral to pathology associated with the most serious diseases in western society, including heart disease, stroke, and cancer metastasis, as well as disorders involving inflammation and immunity. The underlying mechanisms for these involve mechanical forces, molecular interactions and cellular properties acting synergistically in ways that are uniquely addressed by this program.