Control of leukocyte emigration in reperfused myocardium

项目3：再灌注心肌细胞中白细胞迁移的控制项目3将其长期目标集中在中性粒细胞和单核细胞迁移到炎症部位并与实质细胞相互作用的机制上。该项目已经开发了一些体外实验模型，用于识别可能在再灌注心肌中起作用的机制。这些特定的粘附分子，以及响应局部细胞因子和趋化因子而发生的功能变化。该一般方法将在本申请中继续。该项目有两个具体目标，每个目标下有直接和集中的子目标，其与已知存在于再灌注心肌中的状况或因素有关。他们的选择，以填补空白，在我们的理解机制，控制白细胞迁移和功能的心脏。具体目标1-定义白细胞粘附和信号级联在再灌注心肌中的新步骤。该目标的具体焦点将集中在四个领域：a）在流动血液的剪切条件下，粘附分子的选择素家族诱导白细胞功能的改变，所述粘附分子将白细胞束缚到内皮细胞; B）LFA-1（CD 18整联蛋白家族的成员）在嗜中性粒细胞中的广泛功能; c）由心肌ICAM-1支持的白细胞功能（CD 18整合素的配体）与外周小静脉上的ICAM-1形成对比;和d）制瘤素M和IL-15在心肌中的功能贡献，因为它们适用于粘附和信号级联反应。具体目标2-确定调节再灌注心肌中白细胞粘附和信号级联的抗粘附机制。该目标的具体重点将在3个领域：a）使用IL-1和IL-4作为模型的组合细胞因子刺激的抗粘附特性; B）通过再灌注在心肌中上调的抗炎细胞因子的潜在作用，重点是IL-10;和c）可溶性心肌衍生粘附分子，特别是ICAM-1的潜在贡献。

PROJECT 3: Control of Leukocyte Emigration in Reperfused Myocardium Project 3 focuses its long term objective on the mechanisms by which neutrophils and monocytes emigrate into inflammatory sites and interact with parenchymal cells. The project has developed a number of in vitro experimental models of identification The project has developed The project has developed a number of in vitro experimental models for identification of mechanisms that may operate in the reperfused myocardium. These specific adhesion molecules, and the changes in functions that occur in response to local cytokines and chemokines. This general approach will continue in the present application There are two specific aims for this project with immediate and focused sub-aims under each that are linked to condition or factors known to be present in the reperfused myocardium. They are chosen to fill gaps in our understanding of the mechanisms that control leukocyte emigration and function in the heart. Specific Aim 1- Define new steps in the leukocyte adhesion and signaling cascade operate in reperfused myocardium. The specific focus of this aim will be in four areas; a) alterations in leukocyte functions induced by the selectin family of adhesion molecules that tether leukocytes to endothelial cells under conditions of shear by flowing blood; b) the broad functions in neutrophils of LFA-1, a member of the CD18 integrin family; c) the leukocyte functions supported by myocardial ICAM-1 (a ligand for CD18 integrins) in contrast to ICAM-1 on peripheral venules; and d) the functional contributions of oncostatin M and IL-15 in myocardium as they apply to the adhesion and signaling cascade. Specific Aim 2- Define anti-adhesive mechanisms that modulate the leukocyte adhesion and signaling cascade in reperfused myocardium. The specific focus of this aim will be in 3 areas; a) the anti-adhesive properties of combined cytokine stimulation using IL-1 and IL-4 as a model; b) the potential role of anti-inflammatory cytokines up-regulated in the myocardium by reperfusion, with focus on IL-10; and c) the potential contributions of soluble myocardial-derived adhesion molecules, especially ICAM-1.