Richard U. Margolis, MD, PhD

Our research concerns the structure, localization, biosynthesis, and functional roles of proteoglycans in nervous tissue. Proteoglycans are proteins to which a special type of sugar chain, a sulfated glycosaminoglycan, is attached, and 1 to 100 or more such chains may be present on a single proteoglycan core protein. Because proteoglycans are often highly complex molecules containing a number of distinct protein domains and different types of carbohydrate units, individual regions of the molecule may serve different biological functions. Proteoglycans, and the unsulfated glycosaminoglycan hyaluronan, are for the most part present on the cell surface or surrounding cells in the extracellular space, where they are known to interact with other cell surface proteins and extracellular matrix molecules, but we have also demonstrated their presence in the cytoplasm and nucleus. Our interest focuses on the roles of proteoglycans in cell interactions during nervous tissue development and repair after injury, and their regulatory functions in cell growth and differentiation.

Current work includes studies of the nucleocytoplasmic shuttling of the heparan sulfate proteoglycan glypican-1, and its possible role in the transport of growth factors into the nucleus. We have also demonstrated that glypican-1 is a high-affinity ligand of the Slit proteins, which regulate axonal guidance, branching, dendritic development, and neural migration, and it has recently been shown that both glypican-1 and Slit mRNA are strongly up-regulated and co-expressed in the reactive astrocytes of injured adult brain, suggesting a possible function of glypican-Slit protein complexes or proteolytic processing fragments of Slit in the adult CNS (where few axon guidance events occur) as significant components of the inhibitory environment after injury. Because the interaction with Slit proteins is mediated by the heparan sulfate chains of glypican-1, we are currently exploring the use of relatively low molecular weight heparan sulfate-mimetics as a novel approach to promoting axonal regeneration after spinal cord injury. Other studies concern the production of proteoglycans and related extracellular matrix proteins by neural stem cells, and their effects on stem cell survival and differentiation.