User:Steven Rosen

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We currently are pursuing two main areas of research: 1) molecular mechanisms of leukocyte trafficking; and 2) the role of heparan sulfate degrading sulfatases in cancer. A major emphasis of the trafficking studies has been L-selectin, a lectin-type receptor on leukocytes that mediates leukocyte adhesion to activated endothelium. This receptor recognizes endothelial ligands that contain key sulfated carbohydrate determinants. We are studying the sulfotransferases that synthesize these ligands and how these enzymes are regulated. We are studying the role of the L-selectin/endothelial ligand adhesion system in the recruitment of lymphocytes and other leukocytes to sites of chronic inflammation, in particular joints in rheumatoid arthritis and airways in asthma. We are also interested in the signaling responses that are induced in leukocytes when L-selectin is ligated through interaction with appropriate ligands. The second main direction of the lab concerns two novel sulfatases, called Sulf-1 and Sulf-2 which we cloned and characterized 6 years ago. These enzymes are secreted and act extracellularly. They remove specific internal sulfate residues (i.e., glucosamine-6-sulfate) from heparan sulfate proteoglycans (HSPGs) on the cell surface and in the extracellular matrix. This desulfation step regulates the ability of heparan sulfate chains to bind particular protein ligands and therefore controls the bioavailability of the ligands. Wnt ligands are one of the ligand families that are regulated by the Sulfs. In a number of cancers, this developmental signaling pathway is reactivated where it promotes cell proliferation and survival. We and others have observed the upregulation of Sulf expression in several cancers, including pancreatic, breast and lung adenocarcinomas. Using pancreatic cancer cell lines and non-small cell lung cancer lines, we have shown that the Sulfs facilitate Wnt signaling in these cells and in so doing promotes cell proliferation and survival in vitro and tumorigenicity in nude mice. Since the Sulfs are extracellular enzymes, they could emerge as therapeutic targets for the treatment of pancreatic and lung carcinomas, diseases which have a poor prognosis with current therapies. The Sulfs are also important in development and during wound repair. The latter aspect is being investigated by us in corneal injury models.

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