The Rosen Laboratory

Our Lab’s Research Focus:
Chemical and biological approaches to the molecular mechanisms regulating lymphocyte trafficking

The maintenance of effective host defense depends upon the recirculation of lymphocytes from blood to lymph nodes and returning to blood via lymph. My lab recently described a new molecular mechanism regulating egress of lymphocytes from lymph nodes into lymph and thus blood using reverse pharmacology. A potent compound was identified (FTY720) that induced the disappearance of lymphocytes from peripheral blood. It was phosphorylated to a biologically active and potent molecule that allowed the identification of a molecular target. The mechanism was found to be the activation of a family of G-protein-coupled edg receptors for sphingosine 1-phosphate. We are able to use highly potent picomolar synthetic compounds that activate these receptors at alter lymphocyte trafficking and produce immunosuppression. This mechanism of immunosuppression is of significant interest as a potential novel approach to transplantation rejection and autoimmune diseases including multiple sclerosis. The focus of the laboratory is on using chemical probes of receptor function to elucidate the molecular basis of the control of lymphocyte trafficking, at the level of lymphocytes and endothelial cells, and in the specific tissue microenvironments in lymphoid organs.

Our approaches involve identifying receptors implicated in lymphocyte trafficking, developing chemical agonists and antagonists of receptor function, the evaluation of receptor contribution to cell function in vivo and the identification of transductional and physical changes regulating lymphocyte trafficking in vitro and in intact lymphoid organs by biochemical and imaging methods including confocal scanning microscopy.

These studies are defining fundamental mechanisms of receptors and ligands not previously known to regulate immune function that may have broad clinical impact.

NIH Roadmap Initiative for Chemical Probes of Biological Functions

We were the lead lab in the Scripps Research Institute Molecular Screening Center, a $10.4 million award that was part of the NIH MLSCN Roadmap.  We now are the Comprehensive Center for Chemical Probe Discovery and Optimization in the second phase of the NIH Roadmap Initiative, the Molecular Libraries Probe Production Centers Network.

For further details, please see the following announcements from NIH and TSRI:

NIH Press Release: January 28, 2011

NIH Press Release: June 15, 2005

TSRI News & Views: June 20, 2005 

For information on accessing the NIH MLPCN Roadmap, please contact Steve Brown at sbrown@scripps.edu.

You may also visit the Center’s website at http://molscreen.florida.scripps.edu.