Overview
The surfaces of cells are covered with a dense layer (glycocalyx) of glycoproteins, glycolipids, and proteoglycans. These glycoconjugates bind to various proteins, including growth factors, enzymes, and extracellular matrix proteins, and thereby participate in a wide variety of biological phenomena related to cell differentiation, proliferation and migration, morphogenesis, and normal and pathophysiology. To a large extent these interactions are determined by the structure of the polysaccharide chains (glycans) that distinguish the various subclasses of glycoconjugates. The assembly of these molecules involves many enzymes, substrates and cofactors 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 glycans and biological responses is a major problem in modern cell biology.
Research in my lab utilizes a combination of chemistry, cell biology and genetics to understand the structure and function of sulfated glycosaminoglycans found on proteoglycans. This group of glycans consists of heparan sulfate and chondroitin/dermatan sulfate. We have numerous cell and organismal mutants altered in genes that encode the biosynthetic enzymes and the protein cores on which the chains assemble. Studies of these cell lines and mice bearing conditional and systemic mutations allow us to analyze glycan function in normal physiology and disease. Current work arranged by systems include:
- Proteoglycan Metabolism. Mouse strains are under development lacking specific sulfotransferases involved in heparan and chondroitin/dermatan sulfate assembly (Danyin Song, MS and Patrick Secrest). Other studies include analysis of a family of sulfotransferases that create ligand-binding sites in heparan sulfate and development of mass spectrometry methods to determine proteoglycan structure (Roger Lawrence, PhD and Bryan Thacker, MS). A new study focuses on genome-wide screens for novel genes involved in glycosaminoglycan assembly (Emylie Seamen, PhD and Chelsea Nora, BSc).
- Chemical Biology. In collaboration with Y. Tor’s group in the Department of Chemistry and Biochemistry, we have developed guanidinylated glycosides that bind to proteoglycans and facilitate delivery of high molecular weight cargo into the interior of the cell (Wenyong Tong, PhD). Current studies focus on the delivery of lysosomal enzymes to cells and tissues, with the objective of restoring normal lysosomal degradation. In another study, a high throughput screening for small drug-like molecules that stimulate heparan sulfate synthesis is underway as a segue to developing drugs for treating hereditary multiple exostoses (HME), a pediatric disorder characterized by ectopic growth plates on endochondral bones.
- Lipoprotein Metabolism. Another area of interest concerns the role of proteoglycans in the turnover and clearance of triglyceride-rich lipoproteins (Jon Gonzales, BSc). Recent studies focus on macrophage proteoglycans, foam cell conversion and atherosclerosis (Philip Gordts, PhD).
- Vascular Biology. Projects in this area involve studies of proteoglycans in bacterial infection (Xander van Wijk, PhD). Another project focuses on the role of proteoglycans in receptor assembly in signaling as related to vascular biology and atherosclerosis (Ding Xu, PhD and Jeffrey Young, MS).
The lab currently consists of 6 postdocs/fellows, 4 graduate/research assistants, 3 technicians, and 1 undergraduate. We have lab meeting every week (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. Trainees receive classical training in the chemistry and biochemistry of glycans and modern training in genetics, cell biology and physiology. My door is always open, so stop by anytime.