Selectins are a family of adhesion molecules that control the initial interaction of adhesion molecules that control the initial interaction of leukocytes with the vascular endothelium in lymphoid tissues and sites of acute and chronic inflammaiton. P- and E- selectin are two members of this family that are selectively expressed by endothelial cells in sites of inflammation. Specifically, E-selectin is involved in the migration of neutrophils into sities of acute inflammaiton and unique subsets of lymphocytes into sites of chronic inflammation. The lymphocyte subsets that have the capacity to bind E-selectin represent cells that have undergone conversion to a """"""""memory"""""""" phenotype, including both aopha/beta (ab) and gamma/delta (gd) T cells, and exhibit preferential homing to extralymphoid sites of inflammation. E-selectin glycoprotein ligands that present specific selectin-binding carbohydrate structures in that present specific selectin-binding carbohydrate structures in appropriate fashion to suport cell/cell adhesion on neutrophils have been well defined; however, virtually nothing is known about analogous lymphocyte structures. The investigator has found that E-selectin ligands on human and bovine lymphocytes (the bovine system represents his animal model to study the in vivo relevance of these interactions) are distinct from those expressed by neutrophils. In contrast, the interactio of these cell types with P-selectin is controlled by the same molecule, P-selectin glycoprotein ligand-1 (PSGL-1). In this project the principle investigator intends to confirm these observations by pursuing the following Specific Aims: 1) Confirm that PSGL-1 is the predominant lymphocyte ligand for P-selectin; 2) Compare and contrast the biochemical nature of E-selectin-binding ligands on human and bovine lymphocytes with those expressed by neutrophils; 3) Generate monoclonal antibodies (mAb) against E-selectin-binding ligands to homogeneity, antibodies (mAb) against E-selectin binding ligands isolated from bovine and human lymphocytes; 4) Purify E-selectin-binding ligands to homogeneity, sequence, compare to known ligands, and analyze their capacity to support cell adhesion under physiological flow; 5) Clone cDNAs encoding unique E-selectin ligands; and 6) Evaluate the importance of the E-selectin ligans in different inflammatory lesions in vivo. The results of these studies may reveal new approaches to development of specific inhibitors that can selectively target neutrophil versus lymphocyte recruitment to sites of inflammation involving either P-selectin or E-selectin.
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