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.
