Vascular Relations of Blood Cells and Proteins

描述(由申请人提供)： 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。在西方社会，外周血管功能障碍是与心脏病、中风和癌症转移等最严重疾病相关的病理过程中不可或缺的一部分，也在其他涉及炎症和免疫反应的疾病中发挥重要作用。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和3有一个共同的重点，并使用互补的方法来了解控制中性粒细胞和内皮细胞之间相互作用的基本化学和物理因素，特别是从选择素介导的滚动相互作用到整合素介导的中性粒细胞附着和迁移的转变。特别强调的是将在体外观察到的行为与体内临床相关事件联系起来，从中我们可以获得对粘连调节机制的准确理解(与项目4)。项目2的重点是调节中性粒细胞中黏附分子表达和激活的机制，重点是阴离子转运在调节中所起的作用和确定治疗干预的潜在靶点。在与所有其他项目的合作下，将描述黏附分子表达改变对中性粒细胞黏附的影响。项目4侧重于体内白细胞-内皮细胞相互作用的机制，重点是黏附分子表达的异质性的功能后果，黏附分子表达和流体动力学在白细胞募集中的相对作用(与项目5)，以及钙信号在中性粒细胞-内皮细胞通讯中的作用。项目5使用计算工具(与项目1)和体外人工血管构造来确定流体动力学、细胞-细胞相互作用和细胞变形性(与项目3)在确定白细胞-内皮细胞相互作用的主要部位中的重要性。一个主要的目标(项目4)是开发现实的计算模型，以评估血管几何形状和黏附分子表达的异质性对白细胞捕获的关键作用。

DESCRIPTION (provided by applicant): 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. Peripheral vascular dysfunction is integral to the pathology associated with the most serious diseases in Western society, including heart disease, stroke, and cancer metastasis, and also play a fundamental role in other disorders involving inflammation and immune 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 and 3 have a common focus and employ complementary approaches to understand fundamental chemical and physical factors that govern interactions between neutrophils and endothelium, particularly the transition from selectin-mediated rolling interactions to integrin-mediated neutrophil attachment and migration. A particular emphasis is to relate behaviors observed in vitro, from which we can obtain precise understanding of regulatory mechanisms of adhesion, to clinically relevant events in vivo (with Project 4). Project 2 focuses on mechanisms regulating adhesion molecule expression and activation in neutrophils, with a focus on the role that anion transport plays in that regulation and the identification of potential targets for therapeutic intervention. In collaboration with all other projects, the consequences of altered adhesion molecule expression on neutrophil adhesion will be delineated. Project 4 focuses on the mechanisms underlying leukocyte-endothelial interaction in vivo, with emphasis on the functional consequences of heterogeneities in adhesion molecule expression, the relative roles of adhesion molecule expression and hydrodynamics in leukocyte recruitment (with Project 5) and the role of calcium signaling in neutrophil-endothelial communication. Project 5, uses computational tools (with Project 1) and artificial vascular constructs in vitro to identify the importance of hydrodynamics, cell-cell interactions, and cell deformability (with Project 3) in determining dominant sites of leukocyte-endothelial interactions. A major goal (with Project 4) is to develop realistic computational models to evaluate the critical roles that vascular geometry and heterogeneity in adhesion molecule expression have on leukocyte capture.