ADHESION MOLECULES FOR MONOCYTES IN VASCULAR DISEASE

单核细胞与内皮细胞的相互作用增加似乎是 动脉粥样硬化形成的早期事件。 这一建议是针对一个基本的 了解启动单核细胞的单核细胞-EC相互作用 招聘 内皮细胞表达几种已知的粘附分子 对于单核细胞;然而，目前表征的单核细胞-内皮细胞 细胞粘附途径不是单核细胞特异性的，本身不能解释 体内观察到的单核细胞选择性粘附。 我们制定了两个 主要工作假设，以指导我们的努力，以了解 赋予生理特异性的机制：1）第一种假设 假定存在尚未定义的真正单核细胞特异性粘附 单核细胞粘附所需的参与途径 生理设置。 这一假设已经得到了一些支持 因为我们已经鉴定了一种明显的新分子， 刺激的内皮细胞似乎参与单核细胞 粘连 我们建议克隆和表征这种新的粘附 单核细胞的分子。 ?尽管这种分子的抗体抑制 单核细胞与刺激的内皮细胞结合，大量残留 结合仍然存在，这表明其他粘附途径仍然存在， 定义了 因此，我们还建议产生和选择额外的阻塞 针对活化的内皮细胞的单克隆抗体， 鉴定和表征其它新粘附分子， 单核细胞 进一步的研究将旨在了解功能， 定义的新分子的分子特征。 2)第二 假设单核细胞粘附的特异性不是由 通过单个单核细胞特异性粘附途径，而是通过活性， 内皮细胞识别的多步骤过程，其中特异性是 通过已知和/或新的粘附分子的独特组合来确定。 这种可能性将通过免疫细胞化学表征来解决 表达的新的元素确定以及已知的粘附 实验性或人类早期脂肪条纹内皮上的元素 和动脉粥样硬化病变。 单核细胞-内皮细胞显著特异性的分子基础 相互作用对理解血管分化很有意义， 重塑和炎症介导的血管病理学。

Increased interaction of monocytes with endothelium appears to be among the earliest events in atherogenesis. This proposal is directed at a basic understanding of monocyte-EC interactions that initiate monocyte recruitment. Endothelial cells express several known adhesion molecules for monocytes; however, the currently characterized monocyte-endothelial cell adhesion pathways are not monocyte specific, and cannot per se explain the monocyte-selective adhesion observed in vivo. We have formulated two principal working hypothesis to direct our efforts to understand the mechanisms conferring physiologic specificity: 1) the first hypothesis posits the existence of as-yet-undefined truly monocyte-specific adhesion pathway(s) whose engagement is required for monocyte adhesion under physiologic settings. This hypothesis has already received some support since we have identified an apparently novel molecule expressed by stimulated endothelial cells that appears to be involved in monocyte adhesion. We propose to clone and characterize this novel adhesion molecule for monocytes. ?Although antibodies to this molecule inhibit monocyte binding to stimulated endothelial cells, substantial residual binding remains suggesting that additional adhesion pathways remain to be defined. Thus we also propose to produce and select additional blocking monoclonal antibodies against activated endothelial cells in order to identify and characterize additional novel adhesion molecules for monocytes. Further studies will be aimed at understanding the function and molecular characteristics of novel molecules defined. 2) The second hypothesis is that the specificity of monocyte adhesion is determined not by a single monocyte-specific adhesion pathway, but rather by an active, multi-step process of endothelial cell recognition in which specificity is determined by unique combinations known and/or novel adhesion molecules. This possibility will be addressed by immunocytochemical characterization of expression of novel elements identified as well as known adhesion elements on the endothelium of experimental or human early fatty streaks and atherosclerotic lesions. The molecular basis of the remarkable specificity of monocyte-endothelial interactions is of interest in understanding vascular differentiation, remodelling and inflammation-mediated vascular pathology in general.