Vascular Relations of Blood Cells and Proteins

该项目的主题是力学，化学和流体力学的相互关系，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。五个项目正在进行协同研究，旨在揭示外周血管系统中正常和病理现象的基本机制，重点是嗜中性粒细胞-内皮细胞相互作用。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支配整合素介导的中性粒细胞附着和迁移。特别强调的是将体外观察到的行为（项目1、2和3）与体内临床相关事件（项目2和4）联系起来，在体外我们可以准确了解粘附的调节机制。项目1使用定量模型和分子方法来理解连接趋化因子刺激与整合素激活和流动中细胞固定的信号事件，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进行调节的。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粘附和细胞爬行的起始，并表征导致整合素亲和力和亲合力变化的信号通路的动态。项目4的重点是在体内白细胞-内皮细胞相互作用的机制，重点是粘附分子表达的异质性的功能后果，和白细胞结扎引发的内皮细胞（EC）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相关的机制，特别是关于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4）。除了计算研究以确定异常细胞几何形状对细胞捕获的后果之外。项目5与项目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中最严重的疾病相关的病理学的组成部分，包括心脏病、中风和癌症转移，以及涉及炎症和免疫的病症。这些潜在的机制涉及机械力，分子相互作用和细胞特性协同作用的方式，是唯一解决这个程序。

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.