Research

Research

Our primary interests are in the molecular biology of cell surface molecules governing adhesion to and transmigration through vascular endothelium. It is the vascular barrier that must be breached in the course of normal extravasation of cells into tissue compartments, and to wall off and eliminate foreign insult such as incurred by infectious agents in those tissues. This cellular traffic is responsible for desired and undesired inflammation to proceed when normal cells are involved, and it is likely that similar mechanisms operate through which neoplastic counterparts spread from one tissue to another to form cancer metastases. We have been engaged in the characterization, cloning, and functional attributes of adhesion molecules, including the lymph node homing receptor (LHR, L-selectin) in mouse and man, as well as the cartilage link family member CD44. Our molecular cloning of L-selectin revealed a novel makeup of a tandem collection of protein domains. This unique architecture defines the selectin family of adhesion receptors, and all share functions critical to interactions between circulating cells and the vasculature, and are ultimately responsible for targeting cells to sites throughout the organism.

One of our main goals is to study the role of adhesion receptors and their regulation in autoimmune and chronic inflammatory conditions. We generated mice deficient in L-selectin expression and have elucidated the roles of this molecule in immune responses, and in the generation of hematopoietic and other organ systems. We have further placed this genetic defect in animals with various types of autoimmune syndromes to examine the effect on the outcome of these diseases. In addition, we have identified and are characterizing molecular and biological aspects of a novel adhesion pathway for extravasation of activated lymphocytes involving the cell surface molecule CD44, and have been exploring the role of this pathway during immune and autoimmune responses in animal models and directly under autoimmune settings in man. Recent approaches have included microarray and proteomic technologies. The potential role of these adhesion interactions in cancer cell dissemination and localization are also under investigation.

Our more recent studies in both animal models and human autoimmune conditions have led us to explore the role of this adhesion pathway particularly in regulatory T cells, which are pivotal in controlling responses to infectious agents, to protecting tissues from autoimmune attacks, in allowing tolerance to bone marrow and organ transplantation, and for moderating responses to tumor antigens.