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Overview

The surfaces of cells are covered with a dense layer (glycocalyx) of glycoproteins, glycolipids, and proteoglycans. The individual glycoconjugates bind to growth factors, enzymes, and extracellular matrix proteins, and thereby participate in a wide variety of biological phenomena related to cell differentiation, proliferation, migration and morphogenesis. To a large extent these interactions are determined by the structure and binding properties of the polysaccharide chains (glycans) that distinguish the various classes of glycoconjugates. The assembly of these molecules involves multiple glycosyltransferases and sulfotransferases and differs from the assembly of nucleic acids and proteins in not requiring a template. Understanding how cells organize the assembly process to bring about cell-type specific biological responses is a major problem in modern cell biology.

Research in the lab combines chemistry, biochemistry and genetics to understand the structure and function of glycans of glycoproteins and proteoglycans. Powerful selection methods have been developed to identify mutant cell lines altered in these genes. The cell lines in turn have been useful in studying the biosynthetic pathways and the relationship of glycan structure to ligand binding, cell adhesion and signaling. The corresponding genes have also been targeted in model organisms, which allows us to study glycan function in early development, organ physiology, and disease. Current work arranged by systems include:

• Tumor Biology. Projects include studies of proteoglycans in tumor growth and pathological angiogenesis (Mark Fuster, MD), development of small molecule biosynthetic inhibitors as agents to prevent metastasis (Jillian Brown, PhD and Feng Yang, PhD), and small molecule antagonists of protein-carbohydrate interactions (Manuela Schuksz, MSTP).
• Vascular Biology. Studies include analysis of endothelial proteoglycans (Max Nieuwdorp, MD), angiogenesis (Mark Fuster, MD), and leukocyte trafficking during inflammation (Ding Xu, PhD), and the blood brain barrier (Erin Foley, BMS).
• Lipoprotein Metabolism. Projects focus on our finding that genetic alteration of hepatocyte heparan sulfate proteoglycans causes hypertriglyceridemia (Rusty Bishop, PhD and Kristin Stanford, BMS). We are particularly interested in analyzing genetic variation in proteoglycan expression in patients with hyperlipidemias.
• Proteoglycans in Development. Projects include studies of branching morphogenesis in the mammary gland in mice (Omai Garner, PhD), studies of tissue regerenation (Adam Cadwallader, PhD) and studies of embryonic cytokinesis in C. elegans dependent on chondroitin proteoglycans (Sara Olson, PhD), which are done in collaboration with Karen Oegema in the Ludwig Cancer Institute.
• Proteoglycan Structure and Assembly. Studies include analysis of a family of sulfotransferases that initiate modification of heparan sulfate chains and development of mass spectrometry methods to determine proteoglycan diversity and structure (Roger Lawrence, PhD). Mouse strains are under development lacking major classes and individual proteoglycans (Danyin Song, MS and Megan Dwyer, BSc).

The lab currently consists of 6 postdocs/fellows, 3 graduate students, 2 technicians, and 1 undergraduate. We have lab meeting every week organized by systems (Wednesdays at 9:30 am), a journal club focused on Current Literature in Glycobiology (BIOM 246, Friday at noon), and periodic submeetings to coordinate projects with collaborators on and off campus. Most lab members have two projects, one focused on biochemical studies and a second that involves studies of a model organism. In this way, trainees receive classical training in the chemistry and biochemistry of glycosylation and modern training in genetics, cell biology and physiology. My door is always open, so stop by anytime.

Relevant Publications