During the resolution of inflammation, some monocytes can migrate from the blood into lymphatic vessels via a process termed reverse transmigration. This transmigration can trigger the differentiation of blood monocytes into dendritic cells (DC). In contrast, monocytes that remain in the subendothelium become macrophages. The investigator has modeled this process in vitro through the use of endothelial cell monolayers which are cultured on an underlying collagen matrix. Preliminary studies from the investigator's laboratory have begun to characterize this mutually exclusive differentiation process, and to examine the roles of the transmembrane transporter proteins p-glycoprotein/MDR-1 and MRP on this process. These studies have led to the hypothesis that antagonism of MDR-1, promotes the development of monocytes into macrophages, which concomitantly prevents the differentiation of monocytes into DC and the migration of DC out of the tissues. Furthermore, MRP may transport an arachidonate metabolite, possibly LTC4, that directly participates in the migration and maturation of DC. This new application from a new investigator has 3 specific aims.
The first aim will identify the factors that induce monocytes to become DC in the in vitro model system.
The second aim will determine whether all monocytes, or just a subset of cells, have the capacity to differentiate into DC.
The third aim will explore the roles of the transmembrane transporter proteins in DC migration and maturation.
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