Our primary research interest is the biology of leuckocyte adhesion and migration, particularly interactions mediated by the selectin family of adhesion molecules. The selectins are a family of three carbohydrate-binding proteins expressed on activated endothelium (E- and P-selectin or CD62E and CD62P), leukocytes (L-selectin or CD62L), and activated platelets (P-selectin). The selectins mediate the earliest interactions between leukocytes and endothelium and play a crucial role in recruitment of leukocytes to endothelium and amplification of the inflammatory response. They are involved in the pathogenesis of numerous diseases including autoimmune disease, cardiovascular disorders, tumor metastasis and atherosclerosis.

The best characterized selectin ligand is leukocyte P-selectin Glycoprotein Ligand-1 (PSGL-1). Unique features of PSGL-1 allow it to interact with both P- and L-selectin, and thus it mediates leukocyte-leukocyte, leukocyte-endothelium, and leukocyte-platelet interactions. Our laboratory is examining several questions regarding the biology of interactions between the selectins and PSGL-1.

1. We are exploring the role of the cytoplasmic domain of PSGL-1 in leukocyte adhesion and signaling. We have shown that PSGL-1 interacts with the actin cytoskeleton through interactions between the cytoplasmic tail and moesin, a member of the ERM family of cytoskeletal proteins. This cytoskeletal interaction appears to be essential for cell adhesion, but the molecular basis for this requirement remains undefined. We are taking a number of cell biological and molecular approaches to determine the nature and importance of PSGL-1/cytoskeletal interactions, to delineate the basis for these interactions, and determine their role in adhesion and signaling.


2. We are further defining the structural properties of PSGL-1 required for interactions with both P- and L-selectin. This work is investigating the extent of amino terminus tyrosine sulfation, the role of specific O-linked glycans, and the requirement for PSGL-1 dimerization in mediating rolling interactions with P- and L-selectin. We are also looking at potential membrane reorganization after engagement of PSGL-1 by either P- or L-selectin.


3. We are investigating the hypothesis that PSGL-1 mediates crosstalk between rolling leukocytes and activated endothelium and thus plays a regulatory role in the initiation of "downstream" events during leukocyte-endothelial interactions at inflammatory sites.


4. In addition to being a selectin ligand, PSGl-1 also serves as the attachment and entry receptor for the causative agent of Human Granulocytic Ehrlichiosis (HGE), and we are continuing to identify the structural and molecular features of PSGL-1 required for HGE binding and invasion. We are also using microarray analysis to investigate the host response to HGE infection focusing on HGE mechanisms for survival and proliferation within neutrophils.

Lab Members