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: 6227615
• 负责人: ANTHONY Michael MONTGOMERY
• 金额: $ 13.43万
• 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 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6227615
• 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，已被指定为 免疫球蛋白超家族早期的研究将L1描述为神经细胞 粘附分子（CAM），并证明这种CAM可以支持 各种动态神经过程。尽管它的神经 在这份提案中，有证据表明， 表明L1参与了血管和免疫过程。因此，L1显示为 作为内皮细胞、血小板和 白细胞进一步的新发现表明，L1可能在 血管生成、血栓形成、外渗和 免疫细胞激活。本建议的总体目标是 明确说明L1在免疫和 和血管过程。为实现这一目标，列举了三个主要目标。在 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， 白细胞亚群并定义其分子基础 识别. L1结构将与功能（粘附性和 运动性）通过使用L1融合蛋白，所述融合蛋白结合了 L1的不同功能域。重点将放在 嗜同性L1-L1和嗜异性L1-L2的功能结果 整合素相互作用和鉴定新的结合 机制等在目标2中，目标是评估L1的贡献 各种血管和免疫过程，包括：1） 白细胞的粘附和外渗; 2）白细胞的停滞和粘附 血小板对受损或活化的内皮细胞; 3）诱导 血管生成;和4）免疫细胞活化的共刺激。在 目标#3，将解决重要的相关问题，包括 鉴定或调节L1表达的因子或机制， 内皮水平和功能评估 翻译后L1裂解的后果。另一个目的是 以证实L1和某些自身免疫性血管炎之间的联系 并评估L1作为血清学标志物在此类 疾病实现这一建议的目标将有助于解决 我们对L1在免疫和细胞凋亡中的作用的认识存在重大差距。 血管过程，并将扩展L1的功能意义 超出了目前神经系统的描述。