Control of leukocyte emigration in reperfused myocardium

项目 3：再灌注心肌中白细胞迁移的控制 项目 3 的长期目标侧重于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。该项目已开发了许多体外鉴定实验模型 该项目已开发了许多体外实验模型，用于鉴定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，每个目标下都有直接且集中的子目标，这些子目标与已知的再灌注心肌中存在的状况或因素相关。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理解空白。具体目标 1 - 定义白细胞粘附和信号级联在再灌注心肌中运作的新步骤。这一目标的具体重点将集中在四个领域； a) 由粘附分子的选择素家族诱导的白细胞功能的改变，该粘附分子在血液流动的剪切条件下将白细胞束缚于内皮细胞； b) LFA-1（CD18 整合素家族的成员）在中性粒细胞中的广泛功能； c) 与外周微静脉上的 ICAM-1 相比，心肌 ICAM-1（CD18 整合素的配体）支持的白细胞功能； d) 制瘤素 M 和 IL-15 在心肌中的功能贡献，因为它们应用于粘附和信号级联。具体目标 2 - 定义调节再灌注心肌中白细胞粘附和信号级联的抗粘附机制。这一目标的具体重点将集中在三个领域； a) 使用IL-1和IL-4作为模型的联合细胞因子刺激的抗粘附特性； 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； c) 可溶性心肌源性粘附分子，尤其是 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.