Vascular Relations of Blood Cells and Proteins

该计划项目的主题是力学、化学和流体动力学之间的相互关系，作为正常和病理的外周血管功能，特别是炎症反应的潜在机制。五个项目致力于协同研究，旨在揭示周围血管系统正常和病理现象的基本机制，重点是中性粒细胞-内皮细胞的相互作用。项目1、2、3和4有一个共同的重点，并采用互补的方法来了解是什么管理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，其中我们可以获得对粘连调节机制的精确了解。项目1使用定量模型和分子方法来了解将趋化因子刺激与整合素激活和流动中的细胞固定联系起来的信号事件，以及中性粒细胞爬行过程中的力产生实验(项目2和3)。项目2使用分子方法来了解整合素亲和力是如何在体外和体内迁移细胞的不同区域中被调节的。项目3使用单细胞实验来揭示分子扩散和表面形貌如何影响黏附和细胞爬行的启动，并表征导致整合素亲和力和亲和力变化的信号通路的动力学。项目4集中于体内白细胞-内皮相互作用的机制，重点是黏附分子表达的异质性的功能后果，以及由白细胞连接引发的内皮细胞(EC)中的信号事件。项目5使用计算和实验方法来研究与细胞捕获有关的机制，特别是关于多粒子流体动力学和剪切力可能影响细胞捕获和细胞激活的方式(项目1和4)。除了用于确定异常细胞几何形状对细胞捕获的影响的计算研究。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。 外周血管功能障碍是与西方社会最严重的疾病相关的病理所不可或缺的，这些疾病包括心脏病、中风和癌症转移，以及涉及炎症和免疫的疾病。这些问题的基本机制包括机械力、分子相互作用和细胞属性，它们以本计划独特的方式协同作用。

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.