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

• 批准号: 7965513
• 负责人: Triantafyllos Chavakis
• 金额: $ 35.35万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7965513
• 关键词: Acute; Adherens Junction; Adhesives; Autoimmune Diseases; Blood; Blood Vessels; Cell Communication; Cell Survival; Cell physiology; Cells; Disease; Endothelial Cells; Endothelium; Extravasation; Gatekeeping; Goals; Homeostasis; Immune; In Vitro; Inflammation; Inflammatory; Investigation; Leukocytes; Lung; Malignant Neoplasms; Mediating; Melanoma Cell; Modeling; Monomeric GTP-Binding Proteins; Mus; Neoplasm Metastasis; Pathologic Neovascularization; Permeability; Play; Process; Regulation; Role; Site; Testing; cancer cell; in vivo; junctional adhesion molecule; melanoma; migration

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, 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. JAM-C inhibition in vivo blocks vascular hyperpermeability as well as pathologic 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, and mice with an endothelial-specific deletion of JAM-C by using several acute inflammation models. b) We found that mouse melanoma cells express JAM-C. JAM-C on melanoma cells and JAM-C on the endothelium were found to mediate the migration of melanoma cells through the endothelium in vitro and thereby melanoma metastasis in vivo. In particular, lung metastasis of melaoma cells injected i.v. was reduced in mice with deletion of JAM-C. Thus, JAM-C contributes to blood-borne melanoma cell metastasis. c) In addition, we have found that JAM-C could regulate endothelial cell survival. This function of JAM-C is currently tested 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，从而介导了体外和体内炎性细胞的跨内皮迁移。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。 JAM-C抑制体内阻断血管过敏性和病理血管生成。我们目前的研究包括：a）通过使用多种急性炎症模型，使用JAM-C - / - 小鼠使用JAM-C - / - 小鼠在体内募集的JAM-C在体内的重要性。 b）我们发现小鼠黑色素瘤细胞表达JAM-C。发现内皮上黑色素瘤细胞和JAM-C上的JAM-C介导了黑色素瘤细胞在体外通过内皮的迁移，从而在体内介导黑色素瘤转移。特别是，注射静脉内的色素瘤细胞的肺转移在删除JAM-C的小鼠中减少了。因此，JAM-C有助于血源性黑色素瘤细胞转移。 c）此外，我们发现JAM-C可以调节内皮细胞存活。 JAM-C的此功能当前在体内进行了测试。