PECAM-INDEPENDENT TRANSENDOTHELIAL MIGRATION

描述(逐字摘自《调查者摘要》)：炎症反应 是一把双刃剑。将白细胞动员到炎症部位 对于感染的快速解决和组织的修复至关重要 由各种伤害造成的损坏。另一方面，大多数人类 病理结果是炎症被误导或持续存在。 结果是宿主组织受到破坏。因此，受到了极大的关注 一直致力于了解炎症的分子基础。 希望能够更好地监管它。以前的研究已经证明了 血小板/内皮细胞黏附分子-2(PECAM)在动脉粥样硬化中的重要作用 跨内皮细胞迁移，即白细胞(WBC)进入 通过挤压紧密相对的内皮细胞而使组织发炎 (EC)衬里血管。然而，即使在最有利的情况下 在某些情况下，阻断PECAM功能只能阻断80%-90%的白细胞内流。 未被阻断的剩余10%-20%的WBC可能代表临床上的 有相当数量的人口处于慢性病。此外，可能会有 PECAM不适用的炎性刺激、血管床或白细胞类型 在瞬变电磁中扮演重要角色。这项提议的目的是识别分子 负责与PECAM无关(PECAM替代)的瞬变电磁机制。我们 已经开发出一种体外试验，可以区分粘连中的一块 透射电子显微镜下可见内皮细胞的根尖表面有WBC。使用这种化验方法，我们有 确定了两个候选分子。在目标1中，我们将进一步描述和描述 EBC和EC结合部新的膜蛋白HEC2的克隆 在透射电子显微镜下。在目标2中，我们将进一步表征一种白细胞β2整合素 在透射电子显微镜中发挥着独特的作用，它独立于其在粘合和 依靠对PECAM的封锁。在目标3中，我们将测试在 在两种急性炎症的小鼠模型中，我们可以区分 在轮回中从一块粘连到粘连。我们已经培育出了小鼠 在PECAM和PECAM不起作用的小鼠中存在遗传缺陷。 这些小鼠将是评估PECAM非依赖性透射电子显微镜的关键。

DESCRIPTION (Verbatim from Investigator's Abstract): The inflammatory response is a double-edged sword. Mobilization of leukocytes to a focus of inflammation is critical for the rapid resolution of infections and restoration of tissue damage resulting from a variety of injuries. On the other hand, most human pathology results from inflammation that is misdirected or prolonged with the result that host tissues are damaged as a result. Therefore, much attention has been directed toward understanding the molecular basis of inflammation in the hope of being better able to regulate it. Previous studies have demonstrated a crucial role for platelet/endothelial cell adhesion molecule-2 (PECAM) in transendothelial migration (TEM), the step in which leukocytes (WBC) enter inflamed tissues by squeezing between the tightly apposed endothelial cells (EC) lining the blood vessels. However, even under the most favorable circumstances, blocking PECAM function only blocks 80-90% of leukocyte influx. The residual 10-20% of WBC that are not blocked may represent a clinically significant population under chronic conditions. Furthermore, there may be inflammatory stimuli, vascular beds, or WBC types for which PECAM does not play a major role in TEM. The aims of this proposal are to identify molecules responsible for PECAM-independent (PECAM alternative) mechanisms of TEM. We have developed an in vitro assay that can distinguish a block in adhesion of WBC tot he apical surface of EC from a block in TEM. Using this assay, we have identified two candidate molecules. In aim 1 we will further characterize and clone HEC2, a novel membrane proteins on EBC and EC junctions that are involved in TEM. In aim 2, we will further characterize a leukocyte beta2 integrin that plays a unique role in TEM that is independent of its role in adhesion and dependent on blockade of PECAM. In aim 3, we will test predictions made in vitro in two murine models of acute inflammation in which we can distinguish a block in adhesion from a block in transmigration. We have generated mice that are genetically deficient in PECAM and mice in which PECAM does not function. These mice will be critical to evaluate PECAM-independent TEM.