Role of ADAMs in Endothelial Inflammatory Response

描述（由申请方提供）：在 炎症过程，如动脉粥样硬化，导致动态 调节膜锚定粘附分子、受体和配体， 调节炎症反应。白细胞募集过程中 炎症反应需要高度调节的白细胞-内皮细胞 包括束缚和滚动，白细胞激活， 白细胞停滞，随后是跨内皮细胞迁移。成员 跨膜蛋白的ADAM（A Disintegrin And Metalloproteinase）家族 含有细胞外金属蛋白酶， “脱落酶”是一组不同的膜锚定蛋白。分子 参与白细胞募集的所有阶段， 并在炎症刺激后被检测为可溶性蛋白质。然而，在这方面， 负责其脱落的酶尚未被鉴定。这 这项提案将研究内皮表达的亚当斯在血管内皮细胞中的作用。 内皮细胞粘附分子和连接蛋白的动态调节 通过询问以下问题来了解白细胞迁移所需的条件：1） 亚当斯在白细胞粘附胞外区脱落中作用 激活的内皮细胞上的分子2)ADAM介导的脱落 内皮连接蛋白调节它们的细胞-细胞相互作用和/或 屏障功能？3)干扰ADAM介导的脱落酶活性 内皮粘附分子和连接蛋白影响白细胞 在体外和体内的募集和迁移？

DESCRIPTION (provided by applicant): Activation of endothelial cells during inflammatory processes, such as atherosclerosis, results in a dynamic regulation of membrane-anchored adhesion molecules, receptors and ligands that modulate the inflammatory response. Leukocyte recruitment during the inflammatory response requires highly regulated leukocyte-endothelial interactions that include tethering and rolling, leukocyte activation, leukocyte arrest, followed by transendothelial cell migration. Members of the ADAM (A Disintegrin And Metalloproteinase) family of transmembrane proteins contain extracellular metalloproteinase that have been shown to be the "sheddases" for a diverse group of membrane-anchored proteins. Molecules involved in all stages of leukocyte recruitment have been shown to be "shed" and are detected as soluble proteins following inflammatory stimuli. However, the enzymes responsible for their shedding have not been identified. This proposal will investigate the role of endothelial-expressed ADAMs in the dynamic regulation of endothelial adhesion molecules and junction proteins required for leukocyte emigration by asking the following questions: 1) What is the contribution of ADAMs to ectodomain shedding of leukocyte adhesion molecules on activated endothelial cells? 2) Does ADAM-mediated shedding of endothelial junction proteins modulate their cell-cell interactions and/or barrier function? 3) How does perturbation of ADAM-mediated sheddase activity for endothelial adhesion molecules and junction proteins affect leukocyte recruitment and transmigration, in vitro and in vivo?