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Current Research

Endothelial-Dependent Mechanisms In Leukocyte Recruitment

 

The overall goal of the research projects in the Luscinskas laboratory is to understand the mechanisms underlying circulating blood mononuclear (monocyte and T cell subsets) leukocyte adhesion and transmigration into tissues during inflammatory and immune responses. Defining the molecular mechanisms of mononuclear leukocyte egress will allow design of rational therapies for treatment of immune diseases.

Our laboratory has developed an in vitro model that allows direct microscopic examination of leukocyte - endothelial interactions live time under defined laminar fluid shear stress conditions that mimic blood flow in small venules. Areas of focus using this model are two-fold. First, dissection of the adhesion mechanisms that support blood monocyte and specific T cell subset adhesive interactions with endothelium under flow.  Second, characterization of endothelial-dependent mechanisms involved in regulation of endothelial cell borders (lateral junctions) during leukocyte transmigration, permeability function and cell-cell adhesion using immunological, biochemical and molecular biological strategies in in vitro and in vivo models of inflammation. 

Our laboratory has taken advantage of the Adenovirus vector gene transfer system (Recombinant Adenovirus-2) to introduce wild and mutated molecules at high levels of expression into human endothelial cells in vitro to address these questions. In particular, to study lateral junction function during leukocyte transmigration, the effort has focused on VE-cadherin (cadherin-5) and Junction Adhesion Molecule (JAM), which cluster to the lateral borders of endothelial monolayers and appear to be involved in the process of leukocyte transendothelial migration. Additional projects examine cytokine (IL-12, IL-4, IL-2) regulation of functional selectin ligand expression on T cell subsets using human blood cells and transgenic mice models; (2) examining the role of specific chemokines (eg., MDC, TARC, MCP-1) in regulating adhesive interactions between T cell subsets and blood monocytes, and endothelium under defined flow conditions.