NOVEL ROLES FOR L1-CAM IN VASCULAR AND IMMUNE PROCESSES

L1-CAM 在血管和免疫过程中的新作用

• 批准号: 6537572
• 负责人: ANTHONY Michael MONTGOMERY
• 金额: $ 27.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537572
• 关键词: angiogenesis; binding sites; biomarker; cell adhesion molecules; cellular immunity; chimeric proteins; gene expression; human tissue; integrins; leukocytes; platelet activation; platelets; posttranslational modifications; protein structure function; vascular endothelium

L1 is a transmembrane glycoprotein that has been assigned to the immunoglobulin superfamily. Early studies describe L1 as a neural cell adhesion molecule (CAM) and demonstrate that this CAM can support a variety of dynamic neurological processes. However, despite its neural designation, evidence is presented in this proposal that clearly implicates L1 in both vascular and immune processes. Thus, L1 is shown to serve as a recognition molecule for endothelial cells, platelets and leukocytes. Further novel findings suggest that L1 may function in processes as diverse as angiogenesis, thrombosis, extravasation and immune cell activation. The overall objective of this proposal is to definitively address the functional significance of L1 in both immune and vascular processes. To achieve this three main aims are cited. In aim #1, the primary objective is to confirm that L1 can serve as a recognition molecule for endothelial cells, platelets and defined subsets of leukocytes and to define the molecular basis of this recognition. L1 structure will be related to function (adhesion and motility) through the use of L1-fusion proteins that incorporate the different functional domains of L1. Emphasis will be given to the functional consequences of both homophilic L1-L1 and heterophilic L1- integrin interactions and to the identification of novel binding mechanisms. In aim #2, the objective is to assess the contribution of L1 to a variety of vascular and immune processes including: 1) the attachment and extravasation of leukocytes; 2) the arrest and adhesion of platelets to damaged or activated endothelium; 3) the induction of angiogenesis; and 4) the co-stimulation of immune cell activation. In aim #3, important related issues will be addressed including the identification or factors or mechanisms that regulate L1 expression at the level of the endothelium and an assessment of the functional consequences of post-translational L1 cleavage. A further objective is to confirm an association between L1 and certain autoimmune vasculitides and to assess the clinical utility of L1 as a serological marker in such diseases. Achieving the aims of this proposal will help to address a significant gap in our knowledge as to the role of L1 in both immune and vascular processes and will extend the functional significance of L1 beyond that currently described in the nervous system.

L1是一种跨膜糖蛋白，它被分配给 免疫球蛋白超家族。早期的研究将L1描述为神经细胞 黏附分子(CAM)，并证明该CAM可以支持 各种动态的神经过程。然而，尽管它的神经 指定，这项提案中提出的证据清楚地表明 L1参与血管和免疫过程。因此，L1被显示为 作为内皮细胞的识别分子，血小板和 白细胞。进一步的新发现表明，L1可能在 过程多种多样，如血管生成、血栓形成、渗出和 免疫细胞被激活。这项提议的总体目标是 明确阐述L1在两种免疫系统中的功能意义 和血管突起。为了实现这一目标，列举了三个主要目标。在……里面 目标#1，主要目标是确认L1可以作为 内皮细胞、血小板的识别分子和已定义的 白细胞的亚群并定义其分子基础 承认。L1结构将与功能相关(粘附性和 运动性)通过使用L1融合蛋白 L1的不同功能结构域。重点将放在 同嗜性L1-L1和异嗜性L1-L1的功能后果 整合素相互作用与新结合的鉴定 机制。在目标2中，目标是评估母语的贡献 各种血管和免疫过程，包括：1) 白细胞的附着和外渗；2)停滞和粘连 血小板损伤或激活内皮细胞；3)诱导 血管生成；4)免疫细胞活化的共同刺激。在……里面 目标3，将解决重要的相关问题，包括 发现或调节L1表达的因素或机制 血管内皮细胞水平及功能评价 翻译后L1分裂的后果。另一个目标是 确认L1和某些自身免疫性血管炎之间的关联 并评价L1作为本病血清标志物的临床应用价值。 疾病。实现这项提案的目标将有助于解决 我们对L1在免疫和免疫中的作用的认识存在显著差距 并将扩展L1的功能意义 超出了目前在神经系统中所描述的。