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 and proliferation, migration and 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 biological responses is a major problem in modern cell biology.
Research in my lab utilizes a combination of chemistry, biochemistry and genetics to understand the structure and function of 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 sulfate and chondroitin/dermatan assembly (Danyin Song, MS and Patrick Secrest, BS). 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). A new study focuses on lysosomal storage disorders and the use of mutants to examine the practicality of substrate reduction therapy (Chris Lamanna, PhD).
- Chemical Biology. We are also interested in the development of small molecule antagonists of heparan sulfate-protein interactions based on surfen, an aminoquiniride. In collaboration with Y. Tor’s group in Chemistry, we are developing guanidinylated glycosides that bind to proteoglycans and facilitate delivery of high molecular weight cargo into the interior of the cell (Stephane Sarrazin, PhD).
- Lipoprotein Metabolism. A primary area of interest concerns the role of proteoglycans in the liver that mediate clearance of lipoproteins. Other studies focus on the role of liver heparan sulfate in lipoprotein clearance (Rusty Bishop, PhD, Kristin Stanford, BMS, Erin Foley, BMS).
- Vascular Biology. Projects include analysis of endothelial proteoglycans in physiological and pathological angiogenesis (Mark Fuster, MD). Another project focuses on vascular leakage (Ding Xu, PhD). A new project is aimed at understanding transport of enzymes across the endothelium in the microvasculature (Jon Gonzales, BMS).
- Morphogenesis and Regeneration. Projects include studies of branching morphogenesis in the mammary gland and the role of proteoglycans in liver regeneration after physical and chemical damage.
The lab currently consists of 5 postdocs/fellows, 3 graduate students, 2 technicians, and 2 undergraduates. 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. 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 glycans and modern training in genetics, cell biology and physiology. My door is always open, so stop by anytime.