The Role of JAM-C in Adhesive Interactions of Immune Cells

JAM-C 在免疫细胞粘附相互作用中的作用

基本信息

批准号：
7733139
负责人：
Triantafyllos Chavakis
金额：
$ 29.74万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

The junctions of the endothelium consist a major barrier for the extravasation of leukocytes during inflammation as well as for the blood-borne metastasis of tumor cells. We have previously identified junctional adhesion molecule-C (JAM-C), and could demonstrate that JAM-C is expressed at the interendothelial junctions and serves as a counter-receptor for neutrophil Mac-1, mediating the transendothelial migration of inflammatory cells in vitro and in vivo. We have recently found that JAM-C regulates endothelial paracellular permeability. In contrast to other transmembrane molecules of the endothelial junctions that act as gatekeepers, JAM-C was identified as the first molecule to mediate an increase in paracellular permeability. JAM-C regulates the activity of the small GTPase Rap1 and thereby the integrity of adherens junctions. Moreover, JAM-C in endothelial cells facilitates stress fiber formation. JAM-C inhibition in vivo blocks the VEGF or histamine induced permeability as well as hypoxia-driven retina angiogenesis. Our current investigations include: a) The importance of JAM-C in leukocyte recruitment in vivo is tested with the use of JAM-C -/- mice, by using several inflammation models, such as chemical peritonitis and lung inflammation. b) We found that melanoma cells express JAM-C. The homophilic interaction of JAM-C, i.e. the interaction between JAM-C on melanoma cells and JAM-C on the endothelium, was found to mediate the migration of melanoma cells through the endothelium in vitro and thereby melanoma metastasis in vivo.

内皮的连接处是炎症期间白细胞渗出以及肿瘤细胞血传播转移的主要障碍。我们先前已经鉴定出连接粘附分子-C（JAM-C），并且可以证明JAM-C在间皮上连接处表达，并用作嗜中性粒细胞MAC-1的反感染者，介导体内和体内炎症细胞的跨性皮细胞的跨内皮迁移。我们最近发现JAM-C调节内皮细胞细胞渗透性。与充当守门人的内皮连接处的其他跨膜分子相反，JAM-C被鉴定为第一个介导细胞细胞通透性增加的分子。 JAM-C调节小GTPase RAP1的活性，从而调节粘附连接的完整性。此外，内皮细胞中的JAM-C促进了应力纤维的形成。 JAM-C抑制体体内阻断VEGF或组胺诱导的渗透性以及缺氧驱动的视网膜血管生成。我们目前的研究包括：a）通过使用多种炎症模型，例如化学腹膜炎和肺部炎症，通过使用JAM-C - / - 小鼠在体内募集的JAM-C在体内的重要性。 b）我们发现黑色素瘤细胞表达JAM-C。发现JAM-C的均匀相互作用，即黑色素瘤细胞上JAM-C与内皮上JAM-C之间的相互作用，可介导黑色素瘤细胞在体外通过内皮细胞的迁移，从而在体内介导黑色素瘤转移。