Control of leukocyte emigration in reperfused myocardium

项目3：控制再灌流心肌中的白细胞迁移项目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。该项目已经开发了多个体外实验模型的识别，该项目已经开发了多个体外实验模型，用于识别可能在再灌注心肌中发挥作用的机制。这些特定的黏附分子，以及局部细胞因子和趋化因子引起的功能变化。这一一般方法将在本申请中继续，该项目有两个具体目标，每个目标下都有与再灌流心肌中存在的状况或已知因素相联系的直接和重点的子目标。选择它们是为了填补我们对控制白细胞迁移和心脏功能的机制的了解的空白。具体目标1-确定在再灌注心肌中白细胞黏附和信号级联反应的新步骤。这一目标的具体焦点将集中在四个方面：a)在血液流动的剪切条件下，将白细胞与内皮细胞捆绑在一起的选择素黏附分子家族所引起的白细胞功能的改变；b)CD18整合素家族成员LFA-1在中性粒细胞中的广泛功能；c)心肌ICAM-1(CD18整合素的配体)支持的白细胞功能与外周小静脉上的ICAM-1相反；以及d)oncostatin M和IL-15在应用于黏附和信号级联时在心肌中的功能贡献。特定目标2-确定调节再灌流心肌中白细胞黏附和信号级联的抗黏附机制。这一目标的具体焦点将集中在三个方面；a)以IL-1和IL-4为模型的联合细胞因子刺激的抗黏附特性；b)再灌注后心肌中抗炎细胞因子上调的潜在作用，重点是IL-10；以及c)可溶性心肌来源黏附分子，特别是ICAM-1的潜在作用。

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.